Vitronectin receptor antagonist pharmaceuticals

ABSTRACT

The present invention describes novel compounds of the formula:  
     (Q) d —L n —C h ,  
     useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The present invention further provides novel compounds useful for imaging atherosclerosis, restenosis, cardiac ischemia, and myocardial reperfusion injury. The present invention still further provides novel compounds useful for the treatment of rheumatoid arthritis. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

FIELD OF THE INVENTION

[0001] The present invention provides novel pharmaceuticals useful forthe diagnosis and treatment of cancer, methods of imaging tumors in apatient, and methods of treating cancer in a patient. Thepharmaceuticals are comprised of a targeting moiety that binds to thevitronectin receptor that is expressed in tumor vasculature, an optionallinking group, and a therapeutically effective radioisotope ordiagnostically effective imageable moiety. The therapeutically effectiveradioisotope emits a gamma ray or alpha particle sufficient to becytotoxic. The imageable moiety is a gamma ray or positron emittingradioisotope, a magnetic resonance imaging contrast agent, an X-raycontrast agent, or an ultrasound contrast agent.

BACKGROUND OF THE INVENTION

[0002] Cancer is a major public health concern in the United States andaround the world. It is estimated that over 1 million new cases ofinvasive cancer will be diagnosed in the United States in 1998. The mostprevalent forms of the disease are solid tumors of the lung, breast,prostate, colon and rectum. Cancer is typically diagnosed by acombination of in vitro tests and imaging procedures. The imagingprocedures include X-ray computed tomography, magnetic resonanceimaging, ultrasound imaging and radionuclide scintigraphy. Frequently, acontrast agent is administered to the patient to enhance the imageobtained by X-ray CT, MRI and ultrasound, and the administration of aradiopharmaceutical that localizes in tumors is required forradionuclide scintigraphy.

[0003] Treatment of cancer typically involves the use of external beamradiation therapy and chemotherapy, either alone or in combination,depending on the type and extent of the disease. A number ofchemotherapeutic agents are available, but generally they all sufferfrom a lack of specificity for tumors versus normal tissues, resultingin considerable side-effects. The effectiveness of these treatmentmodalities is also limited, as evidenced by the high mortality rates fora number of cancer types, especially the more prevalent solid tumordiseases. More effective and specific treatment means continue to beneeded.

[0004] Despite the variety of imaging procedures available for thediagnosis of cancer, there remains a need for improved methods. Inparticular, methods that can better differentiate between cancer andother pathologic conditions or benign physiologic abnormalities areneeded. One means of achieving this desired improvement would be toadminister to the patient a metallopharmaceutical that localizesspecifically in the tumor by binding to a receptor expressed only intumors or expressed to a significantly greater extent in tumors than inother tissue. The location of the metallopharmaceutical could then bedetected externally either by its imageable emission in the case ofcertain radiopharmaceuticals or by its effect on the relaxation rate ofwater in the immediate vicinity in the case of magnetic resonanceimaging contrast agents.

[0005] This tumor specific metallopharmaceutical approach can also beused for the treatment of cancer when the metallopharmaceutical iscomprised of a particle emitting radioisotope. The radioactive decay ofthe isotope at the site of the tumor results in sufficient ionizingradiation to be toxic to the tumor cells. The specificity of thisapproach for tumors minimizes the amount of normal tissue that isexposed to the cytotoxic agent and thus may provide more effectivetreatment with fewer side-effects.

[0006] Previous efforts to achieve these desired improvements in cancerimaging and treatment have centered on the use of radionuclide labeledmonoclonal antibodies, antibody fragments and other proteins orpolypeptides that bind to tumor cell surface receptors. The specificityof these radiopharmaceuticals is frequently very high, but they sufferfrom several disadvantages. First, because of their high molecularweight, they are generally cleared from the blood stream very slowly,resulting in a prolonged blood background in the images. Also, due totheir molecular weight they do not extravasate readily at the site ofthe tumor and then only slowly diffuse through the extravascular spaceto the tumor cell surface. This results in a very limited amount of theradiopharmaceutical reaching the receptors and thus very low signalintensity in imaging and insufficient cytotoxic effect for treatment.

[0007] Alternative approaches to cancer imaging and therapy haveinvolved the use of small molecules, such as peptides, that bind totumor cell surface receptors. An In-111 labeled somatostatin receptorbinding peptide, In-111-DTPA-D-Phe¹-octeotide, is in clinical use inmany countries for imaging tumors that express the somatostatin receptor(Baker, et al. Life Sci., 1991, 49, 1583-91 and Krenning, et al., Eur.J. Nucl. Med., 1993, 20, 716-31). Higher doses of thisradiopharmaceutical have been investigated for potential treatment ofthese types of cancer (Krenning, et al., Digestion, 1996, 57, 57-61).Several groups are investigating the use of Tc-99m labeled ananlogs ofIn-111-DTPA-D-Phe¹-octeotide for imaging and Re-186 labeled analogs fortherapy (Flanagan, et al., U.S. Pat. No. 5,556,939, Lyle, et al., U.S.Pat. No. 5,382,654, and Albert et al., U.S. Pat. No. 5,650,134).

[0008] Angiogenesis is the process by which new blood vessels are formedfrom pre-existing capillaries or post capillary venules; it is animportant component of a variety of physiological processes includingovulation, embryonic development, wound repair, and collateral vasculargeneration in the myocardium. It is also central to a number ofpathological conditions such as tumor growth and metastasis, diabeticretinopathy, and macular degeneration. The process begins with theactivation of existing vascular endothelial cells in response to avariety of cytokines and growth factors. Tumor released cytokines orangiogenic factors stimulate vascular endothelial cells by interactingwith specific cell surface receptors for the factors. The activatedendothelial cells secrete enzymes that degrade the basement membrane ofthe vessels. The endothelial cells then proliferate and invade into thetumor tissue. The endothelial cells differentiate to form lumens, makingnew vessel offshoots of pre-existing vessels. The new blood vessels thenprovide nutrients to the tumor permitting further growth and a route formetastasis.

[0009] Under normal conditions, endothelial cell proliferation is a veryslow process, but it increases for a short period of time duringembryogenesis, ovulation and wound healing. This temporary increase incell turnover is governed by a combination of a number of growthstimulatory factors and growth suppressing factors. In pathologicalangiogenesis, this normal balance is disrupted resulting in continuedincreased endothelial cell proliferation. Some of the proangiogenicfactors that have been identified include basic fibroblast growth factor(bFGF), angiogenin, TGF-alpha, TGF-beta, and vascular endothelium growthfactor (VEGF). While interferon-alpha, interferon-beta andthrombospondin are examples of angiogenesis suppressors.

[0010] The proliferation and migration of endothelial cells in theextracellular matrix is mediated by interaction with a variety of celladhesion molecules (Folkman, J., Nature Medicine, 1995, 1, 27-31).Integrins are a diverse family of heterodimeric cell surface receptorsby which endothelial cells attach to the extracellular matrix, eachother and other cells. The integrin α_(v)β₃ is a receptor for a widevariety for a wide variety of extracellular matrix proteins with anexposed tripeptide Arg-Gly-Asp moiety and mediates cellular adhesion toits ligand: vitronectin, fibronectin, and fibrinogen, among others. Theintegrin α_(v)β₃ is minimally expressed on normal blood vessels, but issignificantly upregulated on vascular cells within a variety of humantumors. The role of the α_(v)β₃ receptors is to mediate the interactionof the endothelial cells and the extracellular matrix and facilitate themigration of the cells in the direction of the angiogenic signal, thetumor cell population. Angiogenesis induced by bFGF or TNF-alpha dependon the agency of the integrin α_(v)β₃, while angiogenesis induced byVEGF depends on the integrin α_(v)β₃ (Cheresh et. al., Science, 1955,270, 1500-2). Induction of expression of the integrins α₁β₁ and α₂β₁ onthe endothelial cell surface is another important mechanism by whichVEGF promotes angiogenesis (Senger, et. al., Proc. Natl. Acad, Sci USA,1997, 84, 13612-7).

[0011] Angiogenic factors interact with endothelial cell surfacereceptors such as the receptor tyrosine kinases EGFR, FGFR, PDGFR,Flk-1/KDR, Flt-1, Tek, tie, neuropilin-1, endoglin, endosialin, and Axl.The receptors Flk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF andthese interactions play key roles in VEGF-induced angiogenesis. The Tiesubfamily of receptor tyrosine kinases are also expressed prominentlyduring blood vessel formation.

[0012] Because of the importance of angiogenesis to tumor growth andmetastasis, a number of chemotherapeutic approaches are being developedto interfere with or prevent this process. One of these approaches,involves the use of anti-angiogenic proteins such as angiostatin andendostatin. Angiostatin is a 38 kDa fragment of plasminogen that hasbeen shown in animal models to be a potent inhibitor of endothelial cellproliferation. (O'Reilly et. al., Cell, 1994, 79, 315-328) Endostatin isa 20 kDa C-terminal fragment of collagen XVIII that has also been shownto be a potent inhibitor. (O'Reilly et. al., Cell, 1997, 88, 277-285)Systemic therapy with endostatin has been shown to result in stronganti-tumor activity in animal models. However, human clinical trials ofthese two chemotherapeutic agents of biological origin have beenhampered by lack of availability.

[0013] Another approach to anti-angiogenic therapy is to use targetingmoieties that interact with endothelial cell surface receptors expressedin the angiogenic vasculature to which are attached chemotherapeuticagents. Burrows and Thorpe (Proc. Nat. Acad. Sci, USA, 1993, 90,8996-9000) described the use of an antibody-immunotoxin conjugate toeradicate tumors in a mouse model by destroying the tumor vasculature.The antibody was raised against an endothelial cell class II antigen ofthe major histocompatibility complex and was then conjugated with thecytotoxic agent, deglycosylated ricin A chain. The same group (Clin.Can. Res., 1995, 1, 1623-1634) investigated the use of antibodies raisedagainst the endothelial cell surface receptor, endoglin, conjugated todeglycosylated ricin A chain. Both of these conjugates exhibited potentanti-tumor activity in mouse models. However, both still sufferdrawbacks to routine human use. As with most antibodies or other large,foreign proteins, there is considerable risk of immunologic toxicitywhich could limit or preclude administration to humans. Also, while thevasculature targeting may improve the local concentration of theattached chemotherapeutic agents, the agents still must be cleaved fromthe antibody carrier and be transported or diffuse into the cells to becytotoxic.

[0014] Thus, it is desirable to provide anti-angiogenic pharmaceuticalsand tumor or new vasculature imaging agents which do not suffer frompoor diffusion or transportation, possible immunologic toxicity, limitedavailability, and/or a lack of specificity.

[0015] Another application of anti-angiogenic therapy is in treatingrheumatoid arthritis (RA). In RA, the ingrowth of a highly vascularizedpannus is caused by the excessive production of angiogenic factors bythe infiltrating macrophages, immune cells, or inflammatory cells.Therefore, it is desirable to have new pharmaceuticals to destroy thehighly vascularized pannus that results and thus treat the disease.

[0016] There is also a growing interest in therapeutic angiogenesis toimprove blood flow in regions of the body that have become ischemic orpoorly perfused. Several investigators are using growth factorsadministered locally to cause new vasculature to form either in thelimbs or the heart. The growth factors VEGF and bFGF are the most commonfor this application. Recent publications include: Takeshita, S., et.al., J. Clin. Invest., 1994, 93, 662-670; and Schaper, W. and Schaper,J., Collateral Circulation:Heart, Brain, Kidney, Limbs, Kluwer AcademicPublishers, Boston, 1993. The main applications that are underinvestigation in a number of laboratories are for improving cardiacblood flow and in improving peripheral vessal blood flow in the limbs.For example, Henry, T. et. al. (J. Amer. College Cardiology, 1998, 31,65A) describe the use of recombinant human VEGF in patients forimproving myocardial perfusion by therapeutic angiogenesis. Patientsreceived infusions of rhVEGF and were monitored by nuclear perfusionimaging 30 and 60 days post treatment to determine improvement inmyocardial perfusion. About 50% of patients showed improvement bynuclear perfusion imaging whereas 5/7 showed new collatoralization byangiography. Thus, it is desirable to discover a method of monitoringimproved cardiac blood flow which is targeted to new collateral vesselsthemselves and not, as in nuclear perfusion imaging, a regionalconsequence of new collateral vessels.

[0017] The detection, imaging and diagnosis of a number ofcardiovascular diseases need to be improved, including restenosis,atherosclerosis, myocardial reperfusion injury, and myocardial ischemia,stunning or infarction. It has recently been determined that in all ofthese disease conditions, the integrin receptor αvβ3 plays an importantrole.

[0018] For example, in the restenosis complication that occurs in˜30-50% of patients having undergone angioplasty or stent placement,neointimal hyperplasia and ultimate reocclusion is caused byaggressively proliferating vascular smooth muscle cells that expressαvβ3. (Cardiovascular Res., 1997, 36, 408-428; DDT, 1997, 2, 187-199;Current Pharm. Design, 1997, 3, 545-584).

[0019] Atherosclerosis proceeds from an intial endothelial damage thatresults in the recruitment and subintimal migration of monocytes at thesite of the injury. Growth factors are released which induce medialsmooth muscle cells to proliferate and migrate to the intimal layer. Themigrating smooth muscle cells express αvβ3.

[0020] In reperfusion injury, neutrophil transmigration is integrindependent and the integrins moderate initial infiltration into theviable border zone. The induction of α5β1, α4β1 and αvβ5 in infiltratingneutrophils occurs within 3 to 5 hours after reperfusion as neutrophilsmove from the border zone to the area of necrosis. (Circulation, 1999,100, I-275).

[0021] Acute or chronic occlusion of a coronary artery is known toresult in angiogenesis in the heart as native collateral vessels arerecruited to attempt to relieve the ischemia. However, even a gradualocclusion usually results in areas of infarction as the resultingangiogenesis is not sufficient to prevent damage. Cardiac angiogenesishas been associated with increased expression of the growth factors VEGFand FGF and the upregulation of the growth factor receptors flt-1 andflk-1/KDR. (Drugs, 1999, 58, 391-396)

SUMMARY OF THE INVENTION

[0022] It is one object of the present invention to provide improvedanti-angiogenic pharmaceuticals, comprised of a targeting moiety thatbinds to the vitronectin receptor that is expressed in tumorneovasculature, an optional linking group, and a radioisotope. Thevitronectin receptor binding compounds target the radioisotope to thetumor neovasculature. The beta or alpha-particle emitting radioisotopeemits a cytotoxic amount of ionizing radiation which results in celldeath. The penetrating ability of radiation obviates the requirementthat the cytotoxic agent diffuse or be transported into the cell to becytotoxic.

[0023] It is another object of the present invention to providepharmaceuticals to treat rheumatoid arthritis. These pharmaceuticalscomprise a targeting moiety that binds to a receptor that is upregulatedduring angiogenesis, an optional linking group, and a radioisotope thatemits cytotoxic radiation (i.e., beta particles, alpha particles andAuger or Coster-Kronig electrons). In rheumatoid arthritis, the ingrowthof a highly vascularized pannus is caused by the excessive production ofangiogenic factors by the infiltrating macrophages, immune cells, orinflammatory cells. Therefore, the radiopharmaceuticals of the presentinvention that emit cytotoxic radiation could be used to destroy the newangiogenic vasculature that results and thus treat the disease.

[0024] It is another object of the present invention to provide imagingagents, comprised of vitronectin receptor binding compounds conjugatedto an imageable moiety, such as a gamma ray or positron emittingradioisotope, a magnetic resonance imaging contrast agent, an X-raycontrast agent, or an ultrasound contrast agent. These imaging agentsare useful for imaging tumor neovasculature, therapeutic angiogenesisinterventions in the heart, natural angiogenic processes in response toacute or chronic coronary vessel occlusion, restenosis post-angioplasty,atherosclerosis and plaque formation, and reperfusion injury.

[0025] It is another object of the present invention to providecompounds useful for preparing the pharmaceuticals of the presentinvention. These compounds are comprised of a non-peptide quinolonecontaining targeting moiety that binds to a receptor that is upregulatedduring angiogenesis or during cardiovascular diseases, Q, an optionallinking group, L_(n), and a metal chelator or bonding moiety, C_(h). Thecompounds may have one or more protecting groups attached to the metalchelator or bonding moiety. The protecting groups provide improvedstability to the reagents for long-term storage and are removed eitherimmediately prior to or concurrent with the synthesis of theradiopharmaceuticals. Alternatively, the compounds of the presentinvention are comprised of a peptide or peptidomimetic targeting moietythat binds to a receptor that is upregulated during angiogenesis orduring cardiovascular diseases, Q, an optional linking group, L_(n), anda surfactant, S_(f).

[0026] The pharmaceuticals of the present invention may be used fordiagnostic and/or therapeutic purposes. Diagnostic radiopharmaceuticalsof the present invention are pharmaceuticals comprised of adiagnostically useful radionuclide (i.e., a radioactive metal ion thathas imageable gamma ray or positron emissions). Therapeuticradiopharmaceuticals of the present invention are pharmaceuticalscomprised of a therapeutically useful radionuclide, a radioactive metalion that emits ionizing radiation such as beta particles, alphaparticles and Auger or Coster-Kronig electrons.

[0027] The pharmaceuticals comprising a gamma ray or positron emittingradioactive metal ion are useful for imaging tumors and by gammascintigraphy or positron emission tomography. The pharmaceuticalscomprising a gamma ray or positron emitting radioactive metal ion arealso useful for imaging therapeutic angiogenesis, natural angiogenicprocesses in response to acute or chronic coronary vessel occlusion,restenosis post-angioplasty, atherosclerosis and plaque formation, andreperfusion injury by gamma scintigraphy or positron emissiontomography. The pharmaceuticals comprising a particle emittingradioactive metal ion are useful for treating cancer by delivering acytotoxic dose of radiation to the tumors. The pharmaceuticalscomprising a particle emitting radioactive metal ion are also useful fortreating rheumatoid arthritis by destroying the formation of angiogenicvasculature. The pharmaceuticals comprising a paramagnetic metal ion areuseful as magnetic resonance imaging contrast agents. Thepharmaceuticals comprising one or more X-ray absorbing or “heavy” atomsof atomic number 20 or greater are useful as X-ray contrast agents. Thepharmaceuticals comprising a microbubble of a biocompatible gas, aliquid carrier, and a surfactant microsphere, are useful as ultrasoundcontrast agents.

DETAILED DESCRIPTION OF THE INVENTION

[0028] [1] Thus, in a first embodiment, the present invention provides anovel compound, comprising: a targeting moiety and a chelator, whereinthe targeting moiety is bound to the chelator, is a quinolonenonpeptide, and binds to a receptor that is upregulated duringangiogenesis and the compound has 0-1 linking groups between thetargeting moiety and chelator.

[0029] [2] In a preferred embodiment, the receptor is the integrinα_(v)β₃ or α_(v)β₅ and the compound is of the formula:

(Q)_(d)—L_(n)—C_(h) or (Q)_(d)—L_(n)—(C_(h))_(d′)

[0030] wherein, Q is a compound of Formula (II):

[0031] including stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, or pharmaceutically acceptable salt orprodrug forms thereof wherein:

[0032] R^(1e) is selected from:

[0033] A^(e) is —CH₂— or —N(R^(10e))—;

[0034] A^(1e) and B^(e) are independently —CH₂— or —N(R^(10e))—;

[0035] D^(e) is —N(R^(10e))— or —S—;

[0036] E^(e)-F^(e) is —C(R^(2e))═C(R^(3e))— or —C(R^(2e))₂C(R^(3e))₂—;

[0037] J^(e) is —C(R^(2e))— or —N—;

[0038] K^(e), L^(e) and M^(e) are independently —C(R^(2e))— or—C(R^(3e))—;

[0039] R^(2e) and R^(3e) are independently selected from:

[0040] H, C₁-C₄ alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,arylcarbonyl, and aryl substituted with 0-4 R^(7e),

[0041] alternatively, when R^(2e) and R^(3e) are substituents onadjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂;

[0042] R^(2ae) is selected from:

[0043] H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy) carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

[0044] R^(7e) is selected from:

[0045] H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-,(C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e), SO₂NR^(10e)R^(11e),OR^(10e), and N(R^(11e))R^(12e);

[0046] U^(e) is selected from:

[0047] —(CH₂)_(n) ^(e)—, (CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —(CH₂)_(n)^(e)N(R¹²)(CH₂)_(m) ^(e)—, NH(CH₂)_(n) ^(e)—, —(CH₂)_(n)^(e)C(═O)(CH₂)_(m) ^(e)—, —(CH₂)_(n) ^(e)S(O)_(p) ^(e)(CH₂)_(m) ^(e)—,—(CH₂)_(n) ^(e)NHNH(CH₂)_(m) ^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)_(n)^(e)—, —C(═O)N(R^(10e))—, and —N(R^(10e))S(O)_(p) ^(e)—;

[0048] G^(e) is N or CR^(19e);

[0049] W^(e) is —C(═O)—N(R^(10e))—(C₁-C₃ alkylene)-, in which thealkylene group is substituted by R^(8e) and by R^(9e):

[0050] R^(8e) and R^(9e) are independently selected from:

[0051] H, CO₂R^(18be), C(═O)R^(18be), CONR¹⁷R^(18be),

[0052] C₁-C₁₀ alkyl substituted with 0-1 R^(6e),

[0053] C₂-C₁₀ alkenyl substituted with 0-1 R^(6e),

[0054] C₂-C₁₀ alkynyl substituted with 0-1 R^(6e),

[0055] C₃-C₈ cycloalkyl substituted with 0-1 R^(6e),

[0056] C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e), (C₁-C₁₀ alkyl)carbonyl,

[0057] C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

[0058] phenyl substituted with 0-3 R^(6e),

[0059] naphthyl substituted with 0-3 R^(6e),

[0060] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e),

[0061] C₁-C₁₀ alkoxy substituted with 0-2 R^(7e),

[0062] hydroxy, nitro, —N(R^(10e))R^(11e), —N(R^(16e))R^(17e),aryl(C₀-C₆ alkyl)carbonyl, aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl),CONR^(18ae)R^(20e), SO₂R^(18ae), and SO₂NR^(18ae)R^(20e),

[0063] providing that any of the above alkyl, cycloalkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R^(7e);

[0064] R^(6e) is selected from:

[0065] H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀alkylcarbonyl, —N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be),C(═O)R^(18be), CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O) R^(10e), NR^(10e)C(═O) OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p)R^(11e), SO₂NR^(10e)R^(11e),

[0066] aryl substituted with 0-3 groups selected from halogen, C₁-C₆alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂,

[0067] aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me,and —NMe₂, and

[0068] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0069] R^(10e) is selected from:

[0070] H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl, (C₃-C₁₁cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkyl substituted with0-2 R^(6e);

[0071] R^(11e) is selected from:

[0072] H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R^(4e);

[0073] R^(4e) is selected from:

[0074] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,(C₁-C₁₀ alkyl)carbonyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, andheteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

[0075] alternatively, when R^(10e) and R^(11e) are both substituents onthe same nitrogen atom (as in —NR^(10e)R^(11e)) they may be takentogether with the nitrogen atom to which they are attached to form aheterocycle selected from:

[0076] 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;

[0077] said heterocycle being substituted with 0-3 groups selected from:C₁-C₆ alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆alkyl)carbonyl, (C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,aryl(C₁-C₄ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

[0078] R^(12e) is selected from:

[0079] H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl (C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl,arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl,heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, and aryl(C₁-C₆alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and nitro;

[0080] R^(16e) is selected from:

[0081] —C(═O)OR^(18ae), —C(═O)R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), —C(═O)NHC(═O)R^(18be), C(═O)NHC(═O)OR^(18ae),—C(═O)NHSO₂NHR^(18be), —SO₂R^(18ae), —SO₂N(R^(18be))₂, and—SO₂NHC(═O)OR^(18be);

[0082] R^(17e) is selected from:

[0083] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

[0084] R^(18ae) is selected from:

[0085] C₁-C₈ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e);

[0086] R^(18be) is H or R^(18ae);

[0087] R^(19e) is selected from:

[0088] H, halogen, CF₃, CO₂H, CN, NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₈alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

[0089] R^(20e) is selected from:

[0090] hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

[0091] aryloxy, aryl(C₁-C₄ alkyl)oxy,

[0092] C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0093] C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0094] C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0095] C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0096] C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0097] C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0098] aryloxycarbonyl (C-C₂ alkyl)oxy-,

[0099] aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0100] arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0101] C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy,

[0102] (5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

[0103] (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

[0104] (R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)

[0105] R^(21e) is selected from:

[0106] C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,(C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R^(7e);

[0107] R^(22e) is selected from:

[0108] —C(═O)—R^(18be), —C(═O)N(R^(18be))₂, —C(═O)NHSO₂R^(18ae),C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and —C(═O)NHSO₂NHR^(18be);

[0109] Y^(e) is selected from:

[0110] —COR^(20e), —SO₃H, —PO₃H, —CONHNHSO₂CF₃, —CONHSO₂R^(18ae),—CONHSO₂NHR^(18be), —NHCOCF₃, —NHCONHSO₂R^(18ae), —NHSO₂R^(18ae),—OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₂NHCOR^(18ae), —SO₂NHCO₂R^(18ae),

[0111] m^(e) is 0-2;

[0112] n^(e) is 0-4;

[0113] p^(e) is 0-2;

[0114] r^(e) is 0-2;

[0115] with the following proviso: n^(e) and m^(e) are chosen such thatthe number of atoms connecting R^(1e) and Y^(e) is in the range of 8-14;

[0116] d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0117] d′ is 1-100;

[0118] L_(n) is a linking group having the formula:

((W)_(h)—(CR⁶R⁷)_(g))_(x)—(Z)_(k)—((CR^(6a)R^(7a))_(g)—(W)_(h′))_(x′);

[0119] W is independently selected at each occurrence from the group: O,S, NH, NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O, OC(═O),NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′),(OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′);

[0120] aa is independently at each occurrence an amino acid;

[0121] Z is selected from the group: aryl substituted with 0-3 R¹⁰,C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁰;

[0122] R⁶, R^(6a), R⁷, R^(7a), and R⁸ are independently selected at eachoccurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkylsubstituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzylsubstituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰,NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h);

[0123] R¹⁰ is independently selected at each occurrence from the group:a bond to C_(h), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H,—OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substitutedwith 0-1 R¹², C₁₅ alkoxy substituted with 0-1 R¹², and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹¹;

[0124] R¹¹ is independently selected at each occurrence from the group:H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycolsubstituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹²,cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substitutedwith 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide iscomprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl,bis(phosphonomethyl)glycine, and a bond to C_(h);

[0125] R¹² is a bond to C_(h);

[0126] k is selected from 0, 1, and 2;

[0127] h is selected from 0, 1, and 2;

[0128] h′ is selected from 0, 1, and 2;

[0129] g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0130] g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0131] s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0132] s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0133] s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0134] t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0135] t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0136] x is selected from 0, 1, 2, 3, 4, and 5;

[0137] x′ is selected from 0, 1, 2, 3, 4, and 5;

[0138] C_(h) is a metal bonding unit having a formula selected from thegroup:

[0139] A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected ateach occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH,PR¹³, PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n);

[0140] E is a bond, CH, or a spacer group independently selected at eachoccurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀alkyl-C₆₋₁₀aryl-substituted with 0-3 R¹⁷, and a 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3 R¹⁷;

[0141] R¹³ and R¹⁴ are each independently selected from the group: abond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷,heterocyclo-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, wherein theheterocyclo group is a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O, C₆₋₁₀aryl-C₁₋₁₀ alkyl substituted with 0-3 R¹⁷, C₁₋₁₀alkyl-C₆-10aryl-substituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;

[0142] alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹);

[0143] R¹⁵ and R¹⁶ are each independently selected from the group: abond to L_(n), —OH, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, C₁-C₁₀ alkylsubstituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃₋₁₀cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substitutedwith 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;

[0144] R¹⁷ is independently selected at each occurrence from the group:a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸,—C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —SR¹⁸,—S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂,—C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, 2-(1-morpholino)ethoxy,C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl,C₂-C₆ alkoxyalkyl, aryl substituted with 0-2 R¹⁸, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O;

[0145] R¹⁸, R^(18a), and R¹⁹ are independently selected at eachoccurrence from the group: a bond to L_(n), H, C₁-C₆ alkyl, phenyl,benzyl, C₁-C₆ alkoxy, halide, nitro, cyano, and trifluoromethyl;

[0146] Pg is a thiol protecting group;

[0147] R²⁰ and R²¹ are independently selected from the group: H, C₁-C₁₀alkyl, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkenesubstituted with 0-3 R²³, C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, arylsubstituted with 0-3 R²³, unsaturated 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3

[0148] R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³;

[0149] alternatively, R²⁰ and R²¹, taken together with the divalentcarbon radical to which they are attached form:

[0150] R²² and R²³ are independently selected from the group: H, R²⁴,C₁-C₁₀ alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with0-3 R²⁴, C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with0-3 R²⁴, a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R²⁴, and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴;

[0151] alternatively, R²², R²³ taken together form a fused aromatic or a5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O;

[0152] a and b indicate the positions of optional double bonds and n is0 or 1;

[0153] R²⁴ is independently selected at each occurrence from the group:═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂, —N(R²⁵)₃+, —CH₂OR²⁵, —OC(═O)R²⁵, OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂,—NR²⁶C(═O)R²⁵, —NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂, —NR²⁶SO₂N(R²⁵)₂,—NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵, —S(═O)R^(25a), —SO₂N(R²⁵)₂,—N(R²⁵)₂, NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H, and 2-(1-morpholino) ethoxy;and,

[0154] R²⁵, R^(25a), and R²⁶ are each independently selected at eachoccurrence from the group: hydrogen and C₁-C₆ alkyl;

[0155] and a pharmaceutically acceptable salt thereof.

[0156] [3] In a more preferred embodiment, the present inventionprovides a compound wherein: Q is a compound of Formula (IV):

[0157] including stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, or pharmaceutically acceptable salt orprodrug forms thereof wherein:

[0158] R^(1e) is selected from:

[0159] R^(2e) and R^(3e) are independently selected from:

[0160] H, C₁-C₄ alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,arylcarbonyl, and aryl substituted with 0-4 R^(7e),

[0161] alternatively, when R^(2e) and R^(3e) are substituents onadjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂;

[0162] R^(2ae) is selected from:

[0163] H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy) carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl,arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

[0164] R^(7e) is selected from:

[0165] H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-,(C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e), SO₂NR^(10e)R^(11e),OR^(10e), and N(R^(11e))R^(12e);

[0166] U^(e) is selected from:

[0167] —(CH₂)_(n) ^(e)—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —NH(CH₂)_(n)^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)_(n) ^(e)—, and—C(═O)N(R^(10e))—;

[0168] G^(e) is N or CR^(19e);

[0169] R^(8e) is selected from:

[0170] H, CO₂R^(18be), C(═O)R^(18be), CONR^(17e)R^(18be),

[0171] C₁-C₁₀ alkyl substituted with 0-1 R^(6e),

[0172] C₂-C₁₀ alkenyl substituted with 0-1 R^(6e),

[0173] C₂-C₁₀ alkynyl substituted with 0-1 R^(6e),

[0174] C₃-C₈ cycloalkyl substituted with 0-1 R^(6e),

[0175] C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e),

[0176] (C₁-C₁₀ alkyl) carbonyl,

[0177] C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

[0178] phenyl substituted with 0-3 R^(6e),

[0179] naphthyl substituted with 0-3 R^(6e),

[0180] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0181] R^(9e) is selected from:

[0182] C₁-C₁₀ alkyl substituted with 0-1 R^(6e),

[0183] C₁-C₁₀ alkoxy substituted with 0-2 R^(7e),

[0184] H, nitro, N(R^(11e))R^(12e), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), hydroxy, OR^(22e), —N(R^(10e))R^(11e),—N(R^(16e))R^(17e), aryl(C₀-C₆ alkyl)carbonyl, aryl (C₁-C₆ alkyl),heteroaryl(C₁-C₆ alkyl), CONR^(18ae)R^(20e), SO₂R^(18ae), andSO₂NR^(18ae)R^(20e),

[0185] providing that any of the above alkyl, cycloalkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R^(7e);

[0186] R^(6e) is selected from:

[0187] H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀alkylcarbonyl, —N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be),C(═O)R^(18be), CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p) ^(e)R^(11e), SO₂NR^(10e)R^(11e),

[0188] aryl substituted with 0-3 groups selected from halogen, C₁-C₆alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂,

[0189] aryl (C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me,and —NMe₂, and

[0190] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0191] R^(10e) is selected from:

[0192] H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl, (C₃-C₁₁cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkyl substituted with0-2 R^(6e);

[0193] R^(11e) is selected from:

[0194] H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R^(4e);

[0195] R^(4e) is selected from:

[0196] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl)-,wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

[0197] R^(12e) is selected from:

[0198] H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl (C₁-C₆ alkyl) carbonyl, heteroarylcarbonyl, aryl (C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl,arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl,heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, and aryl(C₁-C₆alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and nitro;

[0199] R^(16e) is selected from:

[0200] —C(═O)OR^(18ae), C(═O)R^(18be), —C(═O)N(R^(18be))₂, —SO₂R^(18ae),and —SO₂N(R^(18be))₂;

[0201] R^(17e) is selected from:

[0202] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

[0203] R^(18ae) is selected from:

[0204] C₁-C₈ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e);

[0205] R^(18be) is H or R^(18ae);

[0206] R^(19e) is selected from:

[0207] H, halogen, CF₃, CO₂H, CN, NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₁₁alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

[0208] R^(20e) is selected from:

[0209] hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₀ cycloalkyloxy,

[0210] aryloxy, aryl(C₁-C₄ alkyl)oxy,

[0211] C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0212] C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0213] C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0214] C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0215] C₃₋₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0216] C₃-C₁₀ cycloalkoxycarbonyl (C₁-C₂ alkyl)oxy-,

[0217] aryloxycarbonyl(C₁₋₂ alkyl) oxy-,

[0218] aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0219] arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0220] C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy,

[0221] (5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

[0222] (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

[0223] (R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)

[0224] R^(21e) is selected from:

[0225] C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R^(7e);

[0226] R^(22e) is selected from:

[0227] —C(═O)—R^(18be), —C(═O)N(R^(18be))₂, —C(═O)NHSO₂R^(18ae),C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and —C(═O)NHSO₂NHR^(18be);

[0228] m^(e) is 0-2;

[0229] n^(e) is 0-4; and

[0230] p^(e) is 0-2;

[0231] with the following proviso: n^(e) and m^(e) are chosen such thatthe number of atoms connecting R¹ and —COR^(20e) in Formula (IV) is inthe range of 8-14;

[0232] d is selected from 1, 2, 3, 4, and 5;

[0233] d′ is 1-50;

[0234] W is independently selected at each occurrence from the group: O,NH, NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O, OC(═O),NHC(═S)NH, NHC(═O)NH, SO₂, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′),(OCH₂CH₂CH₂)_(s″), (CH₂CH₂CH₂O)_(t), and (aa)_(t′);

[0235] aa is independently at each occurrence an amino acid;

[0236] Z is selected from the group: aryl substituted with 0-1 R¹⁰,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-1 R¹⁰;

[0237] R⁶, R^(6a), R⁷, R^(7a), and R⁸ are independently selected at eachoccurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substitutedwith 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzyl substituted with 0-1R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹,NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h);

[0238] k is 0 or 1;

[0239] s is selected from 0, 1, 2, 3, 4, and 5;

[0240] s′ is selected from 0, 1, 2, 3, 4, and 5;

[0241] s″ is selected from 0, 1, 2, 3, 4, and 5;

[0242] t is selected from 0, 1, 2, 3, 4, and 5;

[0243] A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected ateach occurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), OH, and abond to L_(n);

[0244] E is a bond, CH, or a spacer group independently selected at eachoccurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, anda 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷;

[0245] R¹³, and R¹⁴ are each independently selected from the group: abond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;

[0246] alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹);

[0247] R¹⁷ is independently selected at each occurrence from the group:a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸,—C(═O)N(R¹⁸)₂, —CH₂OR¹⁸, —OC(═O)R¹⁸, —OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a),—SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a),—OCH₂CO₂H, and 2-(1-morpholino)ethoxy;

[0248] R¹⁸, R^(18a), and R¹⁹ are independently selected at eachoccurrence from the group: a bond to L_(n), H, and C₁-C₆ alkyl;

[0249] R²⁰ and R²¹ are independently selected from the group: H, C₁-C₅alkyl, —CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3 R²³, C₂-C₅ 1-alkynesubstituted with 0-3 R²³, aryl substituted with 0-3 R²³, and unsaturated5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²³;

[0250] alternatively, R²⁰ and R²¹, taken together with the divalentcarbon radical to which they are attached form:

[0251] R²² and R²³ are independently selected from the group: H, andR²⁴;

[0252] alternatively, R²², R²³ taken together form a fused aromatic or a5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O;

[0253] R²⁴ is independently selected at each occurrence from the group:—CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵, —OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂,and —OCH₂CO₂H; and,

[0254] R²⁵ is independently selected at each occurrence from the group:H and C₁-C₃ alkyl.

[0255] [4] In an even more preferred embodiment, the present inventionprovides a compound including stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, or pharmaceutically acceptable salt orprodrug forms thereof wherein:

[0256] R^(1e) is selected from:

[0257] R^(2e) and R^(3e) are independently selected from:

[0258] H, C₁-C₄ alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,arylcarbonyl, and aryl substituted with 0-4 R^(7e),

[0259] alternatively, when R^(2e) and R^(3e) are substituents onadjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂;

[0260] R^(2ae) is selected from:

[0261] H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

[0262] R^(7e) is selected from:

[0263] H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-,(C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e), SO₂NR^(11e)R^(11e),OR^(10e), and N(R^(11e))R^(12e);

[0264] U^(e) is selected from:

[0265] —(CH₂)_(n) ^(e)—, —NH(CH₂)_(n) ^(e)—, —N(R^(10e))C(═O)—, and—NHC(═O)(CH₂)_(n) ^(e);

[0266] G^(e) is N or CR^(19e);

[0267] R^(8e) is H;

[0268] R^(9e) is selected from:

[0269] H, nitro, N(R^(11e))R^(12e), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)c (═O)NR^(10e)R^(11e), NR^(10e)SO₂NR_(10e)R^(11e),NR^(10e)SO₂R^(21e), hydroxy, OR^(22e), —N(R^(10e))R^(11e),—N(R^(16e))R^(17e), aryl (C₀-C₄ alkyl)carbonyl, aryl(C₁-C₄ alkyl),heteroaryl(C₁-C₄ alkyl), CONR^(18ae)R^(20e), SO₂R^(18ae), andSO₂NR^(18ae)R^(20e),

[0270] providing that any of the above alkyl, cycloalkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R^(7e);

[0271] R^(10e) is selected from:

[0272] H, CF₃, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, aryl, (C₃-C₆cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₄ alkyl substituted with0-2 R^(6e);

[0273] R^(6e) is selected from:

[0274] H, C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, nitro, C₁-C₄alkylcarbonyl, —N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be),C(═O)R^(18be), CONR^(17e)R^(18be), OC(═O)R^(11e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O) R^(10e), NR^(10e)C(═O) OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p)R^(11e), SO₂NR^(10e)R^(11e),

[0275] aryl substituted with 0-3 groups selected from halogen, C₁-C₄alkoxy, C₁-C₄ alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂,

[0276] aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃, S(O)_(p) ^(e)Me,and —NMe₂, and

[0277] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0278] R^(11e) is selected from:

[0279] H, hydroxy, C₁-C₄ alkyl, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆cycloalkyl)methyl, C₁-C₄ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₄alkyl substituted with 0-2 R^(4e);

[0280] R^(4e) is selected from:

[0281] H, C₁-C₄ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, and heteroaryl(C₁-C₄ alkyl)-,wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

[0282] R^(12e) is selected from:

[0283] H, C₁-C₄ alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy) carbonyl,phenyl (C₁-C₄ alkyl)-, phenylsulfonyl, phenyloxycarbonyl, andphenyl(C₁-C₄ alkoxy)carbonyl, wherein said phenyl groups are substitutedwith 0-2 substituents selected from the group consisting of C₁-C₄ alkyl,C₁-C₄ alkoxy, halo, CF₃, and nitro;

[0284] R^(16e) is selected from:

[0285] OC(═O)OR^(18ae), —C(═O)R^(18be), —C(═O)N(R^(18be))₂,—SO₂R^(18ae), and —SO₂N(R^(18be) )₂;

[0286] R^(17e) is selected from:

[0287] H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-,aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

[0288] R^(18ae) is selected from:

[0289] C₁-C₈ alkyl optionally substituted with a bond to L_(n), C₃-C₁₀cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e);

[0290] R^(18be) is H or R^(18ae);

[0291] R^(19e) is selected from:

[0292] H, halogen, CF₃, CO₂H, CN, NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

[0293] R^(20e) is selected from:

[0294] hydroxy, C₁-C₆ alkyloxy, C₃-C₆ cycloalkyloxy,

[0295] aryloxy, aryl(C₁-C₄ alkyl)oxy,

[0296] C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0297] C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0298] C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0299] C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0300] C₃-C₁₀ cycloalkoxycarbonyloxy (C₁-C₂ alkyl) oxy-,

[0301] C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0302] aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

[0303] aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0304] arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0305] C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy,

[0306] (5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

[0307] (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

[0308] (R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)

[0309] R^(21e) is selected from:

[0310] C₁-C₄ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R^(7e);

[0311] R^(22e) is selected from:

[0312] —C(═O)—R^(18be), —C(═O)N(R^(18be))₂, —C(═O)NHSO₂R^(18ae),C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and —C(═O)NHSO₂NHR¹ be;

[0313] m^(e) is 0-2;

[0314] n^(e) is 0-4;

[0315] p^(e) is 0-2;

[0316] C_(h) is

[0317] A¹ is selected from the group: OH, and a bond to L_(n);

[0318] A², A⁴, and A⁶ are each N;

[0319] A³, A⁵, and A⁸ are each OH;

[0320] A⁷ is a bond to L_(n) or NH-bond to L_(n);

[0321] E is a C₂ alkyl substituted with 0-1 R¹⁷;

[0322] R¹⁷ is ═O;

[0323] alternatively, C_(h) is

[0324] A¹ is selected from the group: OH, and a bond to L_(n);

[0325] A², A³ and A⁴ are each N;

[0326] A5, A⁶ and A8 are each OH;

[0327] A⁷ is a bond to L_(n);

[0328] E is a C₂ alkyl substituted with 0-1 R¹⁷;

[0329] R¹⁷ is ═O;

[0330] E-A²

[0331] alternatively, C_(h) is

[0332] A¹ is NH₂ or N═C(R²⁰)(R²¹);

[0333] E is a bond;

[0334] A² is NHR¹³;

[0335] R¹³ is a heterocycle substituted with R¹⁷, the heterocycle beingselected from pyridine and pyrimidine;

[0336] R¹⁷ is selected from a bond to L_(n), C(═O)NHR¹⁸ and C(═O) R¹⁸;

[0337] R¹⁸ is a bond to L_(n);

[0338] R²⁴ is selected from the group: —CO₂R²⁵, —OR²⁵, —SO₃H, and—N(R²⁵)₂; and,

[0339] R²⁵ is independently selected at each occurrence from the group:hydrogen and methyl.

[0340] [5] In another even more preferred embodiment, the presentinvention provides a compound including enantiomeric or diastereomericforms thereof, or mixtures of enantiomeric or diastereomeric formsthereof, or pharmaceutically acceptable salt or prodrug forms thereof,wherein Q is selected from the group:

[0341]3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,

[0342]3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0343]3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

[0344]3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

[0345]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0346]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

[0347]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

[0348]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,

[0349]3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0350]3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0351]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0352]3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,

[0353]3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0354]3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0355]3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionicacid,

[0356]3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionicacid,

[0357]3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0358]3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0359]3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0360]3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphen-yl)sulfonylamino)propionicacid,

[0361]3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0362]3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0363]3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0364]3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]pro-pionicacid,

[0365]3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

[0366]3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

[0367]3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,

[0368]3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0369]3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

[0370]3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

[0371]3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,

[0372]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0373]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,

[0374]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

[0375]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,

[0376]3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

[0377]3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0378]3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0379]3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfon-ylamino)propionicacid,

[0380]3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,

[0381]3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,

[0382]3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6-dichlorophenyl)sulfonylamino)propionicacid,

[0383]3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0384]3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionicacid,

[0385]3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0386]3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0387]3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0388]3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0389]3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,

[0390]3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid, and

[0391]3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid.

[0392] [6] In another even more preferred embodiment, the presentinvention provides a compound selected from the group:

[0393]2-(((4-(4-(((3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid;

[0394]3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)-propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicacid;

[0395]2-(((4-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic;

[0396]3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid;

[0397]3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid;

[0398]3-((1-(3-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid;

[0399]2-(2-aza-2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid;

[0400]2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid;

[0401]2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid conjugate; and

[0402]2-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethy1)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid;

[0403] or a pharmaceutically acceptable salt form thereof.

[0404] [7] In a further preferred embodiment, the present inventionprovides a kit comprising a compound of claim 2, or a pharmaceuticallyacceptable salt form thereof and a pharmaceutically acceptable carrier.

[0405] [8] In an even further preferred embodiment, the kit furthercomprises one or more ancillary ligands and a reducing agent.

[0406] [9] In a still further preferred embodiment, the ancillaryligands are tricine and TPPTS.

[0407] [10] In another still further preferred embodiment, the reducingagent is tin(II).

[0408] [11] In a second embodiment, the present invention provides anovel diagnostic or therapeutic metallopharmaceutical composition,comprising: a metal, a chelator capable of chelating the metal and atargeting moiety, wherein the targeting moiety is bound to the chelator,is a quinolone non-peptide and binds to a receptor that is upregulatedduring angiogenesis and the compound has 0-1 linking groups between thetargeting moiety and chelator.

[0409] [12] In a preferred embodiment, wherein the metallopharmaceuticalis a diagnostic radiopharmaceutical, the metal is a radioisotopeselected from the group: ^(99m)TC, ⁹⁵Tc, lllin, ⁶²Cu, ⁶⁴Cu, ⁶⁷Ga, and⁶⁸Ga, and the linking group is present between the non-peptide targetingmoiety and chelator.

[0410] [13] In another preferred embodiment, the targeting moiety is aquinolone non-peptide and the receptor is α_(v)β₆ or α_(v)β₅.

[0411] [14] In another preferred embodiment, the radioisotope is^(99m)Tc or ⁹⁵Tc, the radiopharmaceutical further comprises a firstancillary ligand and a second ancillary ligand capable of stabilizingthe radiopharmaceutical.

[0412] [15] In another preferred embodiment, the radioisotope is^(99m)TC.

[0413] [16] In another preferred embodiment, the radiopharmaceutical isselected from the group:

[0414]^(99m)Tc(2-(((4-(4-(((3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid)(tricine)(TPPTS);

[0415]^(99m)Tc(2-(((4-(3-(N-(3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid)(tricine)(TPPDS);

[0416]^(99m)Tc(3-((1-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid)(tricine)(TPPTS);

[0417]^(99m)Tc(3-((1-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid)(tricine)(TPPTS);

[0418]^(99m)Tc(3-((1-(3-(3-(N-(3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid)(tricine)(TPPTS);

[0419]^(99m)Tc(2-(2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl)diazenido))(tricine)(TPPTS);

[0420]^(99m)Tc(3-{[1-(3-{2-[(6-(diazenido)(3-pyridyl))carbonylamino](2R)-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicacid) (tricine)(TPPTS).

[0421] [17] In another preferred embodiment, the radioisotope is

[0422] [18] In another preferred embodiment, the radiopharmaceutical isselected from the group:

[0423] [19] In another preferred embodiment wherein themetallopharmaceutical is a therapeutic radiopharmaceutical, the metal isa radioisotope selected from the group: ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho,¹⁷⁷Lu, 149P, ⁹⁰Y, ²¹²Bi, 103Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸AU, ¹⁹⁹AU,¹⁶⁹Yb, ¹⁷⁵Yb, 165Dy, ¹⁶⁶Dy, ⁶⁷CU, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir, and thelinking group is present between the non-peptide targeting moiety andchelator.

[0424] [20] In another preferred embodiment, the targeting moiety is aquinolone non-peptide and the receptor is α_(v)β₃ or α_(v)β₅.

[0425] [21] In another preferred embodiment, the radioisotope is ¹⁵³Sm.

[0426] [22] In another preferred embodiment, the radioisotope is ¹⁷⁷Lu.

[0427] [23] In another preferred embodiment, the radiopharmaceutical isselected from the group:

[0428] [24] In another preferred embodiment, the radioisotope is ⁹⁰Y.

[0429] [25] In another preferred embodiment, the radiopharmaceutical isselected from the group;

[0430] [26] In another preferred embodiment wherein themetallopharmaceutical is a MRI contrast agent, the metal is aparamagnetic metal ion selected from the group: Gd(III), Dy(III),Fe(III), and Mn(II), the targeting moiety is a quinolone nonpeptide andthe linking group is present between the targeting moiety and chelator.

[0431] [27] In another preferred embodiment, the targeting moiety isquinolone non-peptide and the receptor is α_(v)β₃ or α_(v)β₅.

[0432] [28] In another preferred embodiment, the metal ion is Gd(III).

[0433] [29] In another preferred embodiment, the contrast agent is

[0434] [30] In another preferred embodiment wherein themetallopharmaceutical is a X-ray contrast agent, the metal is selectedfrom the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy,Cu, Rh, Ag, and Ir, the targeting moiety is a quinolone non-peptide, thereceptor is α_(v)β₃ or α_(v)β₅ and the linking group is present betweenthe targeting moiety and chelator.

[0435] [31] In another preferred embodiment, the present inventionprovides a novel method of treating rheumatoid arthritis in a patientcomprising: administering a therapeutic radiopharmaceutical of claim 19capable of localizing in new angiogenic vasculature to a patient byinjection or infusion.

[0436] [32] In another preferred embodiment, the present inventionprovides a novel method of treating cancer in a patient comprising:administering to a patient in need thereof a therapeuticradiopharmaceutical of claim 19 by injection or infusion.

[0437] [33] In another preferred embodiment, the present inventionprovides a novel method of imaging therapeutic angiogenesis in a patientcomprising: (1) administering a diagnostic radiopharmaceutical, a MRIcontrast agent, or a X-ray contrast agent of claim 11 to a patient byinjection or infusion; (2) imaging the area of the patient wherein thedesired formation of new blood vessels is located.

[0438] [34] In another preferred embodiment, the present inventionprovides a novel method of imaging cancer in a patient comprising: (1)administering a diagnostic radiopharmaceutical of claim 12 to a patientby injection or infusion; (2) imaging the patient using planar or SPECTgamma scintigraphy, or positron emission tomography.

[0439] [35] In another preferred embodiment, the present inventionprovides a novel method of imaging cancer in a patient comprising: (1)administering a MRI contrast agent of claim 26; and (2) imaging thepatient using magnetic resonance imaging.

[0440] [36] In another preferred embodiment, the present inventionprovides a novel method of imaging cancer in a patient comprising: (1)administering a X-ray contrast agent of claim 30; and (2) imaging thepatient using X-ray computed tomography.

[0441] [37] In a third embodiment, the present invention provides anovel compound, comprising: a targeting moiety and a surfactant, whereinthe targeting moiety is bound to the surfactant, is a nonpeptide, andbinds to a receptor that is upregulated during angiogenesis and thecompound has 0-1 linking groups between the targeting moiety andsurfactant.

[0442] [38] In a preferred embodiment, the targeting moiety comprises aquinolone non-peptide and the linking group is present between thetargeting moiety and surfactant.

[0443] [39] In another preferred embodiment, the receptor is theintegrin α_(v)β₃ or α_(v)β₅ and the compound is of the formula:

(Q)_(d)—L_(n)—S_(f)

[0444] wherein, Q is a compound of Formula (II):

[0445] including stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, or pharmaceutically acceptable salt orprodrug forms thereof wherein:

[0446] R^(1e) is selected from:

[0447] A^(e) is —CH₂— or —N(R^(10e))—;

[0448] A^(1e) and B^(e) are independently —CH₂— or —N(R^(10e))—;

[0449] D^(e) is —N(R^(10e))— or —S—;

[0450] E^(e)-F^(e) is —C(R^(2e))═C(R^(3e))— or —C(R^(2e))₂C(R^(3e)) 2—;

[0451] J^(e) is —C(R^(2e))— or —N—;

[0452] K^(e), L^(e) and Me are independently —C(R^(2e))— or —C(R^(3e))—;

[0453] R^(2e) and R^(3e) are independently selected from:

[0454] H, C₁-C₄ alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,arylcarbonyl, and aryl substituted with 0-4 R^(7e),

[0455] alternatively, when R^(2e) and R^(3e) are substituents onadjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂;

[0456] R^(2ae) is selected from:

[0457] H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

[0458] R^(7e) is selected from:

[0459] H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-,(C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e), SO₂NR^(10e)R^(11e),OR^(10e), and N(R^(11e))R^(12e);

[0460] U^(e) is selected from:

[0461] —(CH₂)e—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —(CH₂)_(n)^(e)N(R¹²)(CH₂)_(m) ^(e)—, NH(CH₂)_(n) ^(e)—, —(CH₂)_(n)^(e)C(═O)(CH₂)_(m) ^(e)—, (CH₂)_(n) ^(e)S(O)_(p) ^(e)(CH₂)_(m) ^(e)—,—(CH₂)_(n) ^(e)NHNH(CH₂)_(m) ^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)_(n)^(e)—, —C(═O)N(R^(10e))—, and —N(R^(10e))S(O)_(p) ^(e)—;

[0462] G^(e) is N or CR^(19e);

[0463] W^(e) is —C(═O)—N(R^(10e))—(C₁-C₃ alkylene)-, in which thealkylene group is substituted by R^(8e) and by R^(9e):

[0464] R^(8e) and R^(9e) are independently selected from:

[0465] H, CO₂R^(18be), C(═O)R^(18be), CONR¹⁷R^(18be),

[0466] C₁-C₁₀ alkyl substituted with 0-1 R^(6e),

[0467] C₂-C₁₀ alkenyl substituted with 0-1 R^(6e),

[0468] C₂-C₁₀ alkynyl substituted with 0-1 R^(6e),

[0469] C₃-C₈ cycloalkyl substituted with 0-1 R^(6e),

[0470] C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e),

[0471] (C₁-C₁₀ alkyl)carbonyl,

[0472] C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

[0473] phenyl substituted with 0-3 R^(6e),

[0474] naphthyl substituted with 0-3 R^(6e),

[0475] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e),

[0476] C₁-C₁₀ alkoxy substituted with 0-2 R^(7e),

[0477] hydroxy, nitro, —N(R^(10e))R^(11e), —N(R^(16e))R^(17e),aryl(C₀-C₆ alkyl)carbonyl, aryl(C₃-C₆ alkyl), heteroaryl (C₁-C₆ alkyl),CONR^(18ae)R^(20e), SO₂R^(18ae), and SO₂NR^(18ae)R^(20e),

[0478] providing that any of the above alkyl, cycloalkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R^(7e);

[0479] R^(6e) is selected from:

[0480] H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀alkylcarbonyl, —N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be),C(═O)R^(18be), CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(11e)R^(11e), NR^(10e)C(═O) R^(10e), NR^(10e)C(═O) OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p)R^(11e), SO₂NR^(10e)R^(11e),

[0481] aryl substituted with 0-3 groups selected from halogen, C₁-C₆alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂,

[0482] aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me,and —NMe₂, and

[0483] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0484] R^(10e) is selected from:

[0485] H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl, (C₃-C₁₁cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkyl substituted with0-2 R^(6e);

[0486] R^(11e) is selected from:

[0487] H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,(C₃-C₁₁ cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R^(4e);

[0488] R^(4e) is selected from:

[0489] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,(C₁-C₁₀ alkyl)carbonyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, andheteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

[0490] alternatively, when R^(10e) and R^(11e) are both substituents onthe same nitrogen atom (as in —NR^(10e)R^(11e)) they may be takentogether with the nitrogen atom to which they are attached to form aheterocycle selected from:

[0491] 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; saidheterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl;

[0492] R^(12e) is selected from:

[0493] H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C₁-C₆alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl,C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl (C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl,arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl,heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, and aryl(C₁-C₆alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and nitro;

[0494] R^(16e) is selected from:

[0495] —C(═O)OR^(18ae), —C(═O)R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), —C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae),—C(═O)NHSO₂NHR^(18be), —SO₂R^(18ae), —SO₂N(R^(18be) )₂, and—SO₂NHC(═O)OR^(18be);

[0496] R^(17e) is selected from:

[0497] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

[0498] R^(18ae) is selected from:

[0499] C₁-C₈ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e);

[0500] R^(18be) is H or R^(18ae);

[0501] R^(19e) is selected from:

[0502] H, halogen, CF₃, CO₂H, CN, NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₈alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

[0503] R^(20e) is selected from:

[0504] hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

[0505] aryloxy, aryl(C₁-C₄ alkyl)oxy,

[0506] C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0507] C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0508] C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0509] C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0510] C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0511] C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0512] aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

[0513] aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0514] arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0515] C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy,

[0516] (5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

[0517] (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

[0518] (R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)-;

[0519] R^(21e) is selected from:

[0520] C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃—CO₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R^(7e);

[0521] R^(22e) is selected from:

[0522] —C(═O)—R^(18be), —C(═O)N(R^(18be))₂, —C(═O)NHSO₂R^(18ae),C(═O)NHC(═O) R^(18be), —C(═O)NHC(═O) OR^(18ae) and C(═O)NHSO₂NHR^(18be);

[0523] Y^(e) is selected from:

[0524] —COR^(20e), —SO₃H, —PO₃H, —CONHNHSO₂CF₃, —CONHSO₂R^(18ae),—CONHSO₂NHR^(18be), —NHCOCF₃, —NHCONHSO₂R^(18ae), —NHSO₂R^(18ae),—OPO₃H₂, —OSO₃H, —PO₃H₂, —SO₂NHCOR^(18ae), —SO₂NHCO₂R^(18ae),

[0525] m^(e) is 0-2;

[0526] n^(e) is 0-4;

[0527] p^(e) is 0-2;

[0528] r^(e) is 0-2;

[0529] with the following proviso: n^(e) and m^(e) are chosen such thatthe number of atoms connecting R^(1e) and Y^(e) is in the range of 8-14;

[0530] d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0531] L_(n) is a linking group having the formula:

((W)_(h)—(CR⁶R⁷)_(g))_(x)—(Z)_(k)—((CR^(6a)R⁷)_(g)—(W)_(h′))_(x′);

[0532] W is independently selected at each occurrence from the group: O,S, NH, NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O, OC(═O),NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂O)₂₀₋₂₀₀,(OCH₂CH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);

[0533] aa is independently at each occurrence an amino acid;

[0534] Z is selected from the group: aryl substituted with 0-3 R¹⁰,C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁰;

[0535] R⁶, R^(6a), R⁷, R^(7a), and R⁸ are independently selected at eachoccurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkylsubstituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzylsubstituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰,NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to S_(f);

[0536] R¹⁰ is independently selected at each occurrence from the group:a bond to S_(f), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H,—OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, Cl-s alkyl substitutedwith 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹¹;

[0537] R¹¹ is independently selected at each occurrence from the group:H, alkyl substituted with 0-1 R¹², aryl substituted with 0-1 R¹², a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-1 R¹²,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹², polyalkylene glycolsubstituted with 0-1 R¹², carbohydrate substituted with 0-1 R¹²,cyclodextrin substituted with 0-1 R¹², amino acid substituted with 0-1R¹², polycarboxyalkyl substituted with 0-1 R¹², polyazaalkyl substitutedwith 0-1 R¹², peptide substituted with 0-1 R¹², wherein the peptide iscomprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl,bis(phosphonomethyl)glycine, and a bond to S_(f);

[0538] R¹² is a bond to S_(f);

[0539] k is selected from 0, 1, and 2;

[0540] h is selected from 0, 1, and 2;

[0541] h′ is selected from 0, 1, and 2;

[0542] g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0543] g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0544] t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0545] x is selected from 0, 1, 2, 3, 4, and 5;

[0546] x′ is selected from 0, 1, 2, 3, 4, and 5;

[0547] S_(f) is a surfactant which is a lipid or a compound of theformula:

[0548] A⁹ is selected from the group: OH and OR²⁷;

[0549] A¹⁰ is OR²⁷;

[0550] R²⁷ is C(═O)C₁₋₂₀ alkyl;

[0551] E¹ is C₁₋₁₀ alkylene substituted with 1-3 R²⁸;

[0552] R²⁸ is independently selected at each occurrence from the group:R³⁰, —PO₃H-R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —C(═O)N(R²⁹)₂, —CH₂OR²⁹, —OR²⁹,—N(R²⁹)₂, C₁-C₅ alkyl, and C₂-C₄ alkenyl;

[0553] R²⁹ is independently selected at each occurrence from the group:R³⁰, H, C₁-C₆ alkyl, phenyl, benzyl, and trifluoromethyl;

[0554] R³⁰ is a bond to L_(n);

[0555] and a pharmaceutically acceptable salt thereof.

[0556] [40] In another preferred embodiment, the compound is of theformula:

Q—L_(n)—S_(f)

[0557] wherein, Q is a compound of Formula (IV):

[0558] including stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, or pharmaceutically acceptable salt orprodrug forms thereof wherein:

[0559] R^(1e) is selected from:

[0560] R^(2e) and R^(3e) are independently selected from:

[0561] H, C₁-C₄ alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl),aryl(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl,arylcarbonyl, and aryl substituted with 0-4 R^(7e),

[0562] alternatively, when R^(2e) and R^(3e) are substituents onadjacent atoms, they can be taken together with the carbon atoms towhich they are attached to form a 5-7 membered carbocyclic or 5-7membered heterocyclic aromatic or nonaromatic ring system, saidcarbocyclic or heterocyclic ring being substituted with 0-2 groupsselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃ andNO₂;

[0563] R^(2ae) is selected from:

[0564] H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄ alkyl)-, (C₂-C₇alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl, C₃-C₇cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆ alkylcarbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;

[0565] R^(7e) is selected from:

[0566] H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl, aryl(C₁-C₄ alkyl)-,(C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e), SO₂NR^(10e)R^(11e),OR^(10e), and N(R^(11e))R^(12e);

[0567] U^(e) is selected from:

[0568] —(CH₂)_(n) ^(e)—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —NH(CH₂)_(n)^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)_(n) ^(e)—, and—C(═O)N(R^(10e))—;

[0569] G^(e) is N or CR^(19e);

[0570] R^(8e) is selected from:

[0571] H, CO₂R^(18be), C(═O)R^(18be), CONR^(17e)R^(18be)

[0572] C₁-C₁₀ alkyl substituted with 0-1 R^(6e),

[0573] C₂-C₁₀ alkenyl substituted with 0-1 R^(6e),

[0574] C₂-C₁₀ alkynyl substituted with 0-1 R^(6e),

[0575] C₃-C₈ cycloalkyl substituted with 0-1 R^(6e),

[0576] C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e),

[0577] (C₁-C₁₀ alkyl) carbonyl,

[0578] C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

[0579] phenyl substituted with 0-3 R^(6e),

[0580] naphthyl substituted with 0-3 R^(6e),

[0581] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0582] R^(9e) is selected from:

[0583] C₁-C₁₀ alkyl substituted with 0-1 R^(6e),

[0584] C₁-C₁₀ alkoxy substituted with 0-2 R^(7e),

[0585] H, nitro, N(R^(11e))R^(12e), OC(═O)R^(10e), OR^(11e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), hydroxy, OR^(22e), —N(R^(10e))R^(11e),—N(R^(16e))R^(17e), aryl(C₀-C₆ alkyl)carbonyl, aryl(C₁-C₆ alkyl),heteroaryl(C₁-C₆ alkyl), CONR^(18ae)R^(20e), SO₂R^(18ae), andSO₂NR^(18ae)R^(20e),

[0586] providing that any of the above alkyl, cycloalkyl, aryl orheteroaryl groups may be unsubstituted or substituted independently with1-2 R^(7e);

[0587] R^(6e) is selected from:

[0588] H, C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀alkylcarbonyl, —N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be),C(═O) R^(18be), CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(11e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e)NR^(10e)SO₂R^(21e), S(O)_(p) ^(e)R^(11e), SO₂NR^(10e)R^(11e),

[0589] aryl substituted with 0-3 groups selected from halogen, C₁-C₆alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂,

[0590] aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me,and —NMe₂, and

[0591] a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e);

[0592] R^(10e) is selected from:

[0593] H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, aryl, (C₃-C₁₁cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkyl substituted with0-2 R^(6e);

[0594] R^(11e) is selected from:

[0595] H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R^(4e);

[0596] R^(4e) is selected from:

[0597] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl)-,wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,

[0598] R^(12e) is selected from:

[0599] H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl (C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl,arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl,heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, and aryl(C₁-C₆alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and nitro;

[0600] R^(16e) is selected from:

[0601] —C(═O)OR^(18ae), —C(═O)R^(18be), —C(═O)N(R^(18be))₂,—SO₂R^(18ae), and —SO₂N(R^(18be) )₂;

[0602] R^(17e) is selected from:

[0603] H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-,aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl);

[0604] R^(18ae) is selected from:

[0605] C₁-C₈ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e);

[0606] R^(18be) is H or R^(18ae);

[0607] R^(19e) is selected from:

[0608] H, halogen, CF₃, CO₂H, CN, NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₈alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy;

[0609] R^(20e) is selected from:

[0610] hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy,

[0611] aryloxy, aryl(C₁-C₄ alkyl)oxy,

[0612] C₂-C₁₀ alkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0613] C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0614] C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0615] C₃-C₁₀ cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0616] C₃-C₁₀ cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0617] C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-,

[0618] aryloxycarbonyl(C₁-C₂ alkyl)oxy-,

[0619] aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-,

[0620] arylcarbonyloxy(C₁-C₂ alkyl)oxy-,

[0621] C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy,

[0622] (5-(C₁-C₅ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

[0623] (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

[0624] (R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)-;

[0625] R^(21e) is selected from:

[0626] C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,(C₃-C₁₁cycloalkyl)methyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkylsubstituted with 0-2 R^(7e);

[0627] R^(22e) is selected from:

[0628] —C(═O)—R^(18be), —C(═O)N(R^(18be))₂, —C(═O)NHSO₂R^(18ae),—C(═O)NHC(═O) R^(18be), —C(═O)NHC(═O) OR^(18ae), and—C(═O)NHSO₂NHR^(18be);

[0629] m^(e) is 0-2;

[0630] n^(e) is 0-4; and

[0631] p^(e) is 0-2;

[0632] with the following proviso: n^(e) and m^(e) are chosen such thatthe number of atoms connecting R¹ and —COR^(20e) in Formula (IV) is inthe range of 8-14;

[0633] W is independently selected at each occurrence from the group: O,S, NH, NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O, OC(═O),NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂O)₂₀₋₂₀₀,(OCH₂CH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);

[0634] aa is independently at each occurrence an amino acid;

[0635] Z is selected from the group: aryl substituted with 0-1 R¹⁰,C₃₋₁₀ cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-1 R¹⁰;

[0636] R⁶, R^(6a), R⁷, R^(7a), and R⁸ are independently selected at eachoccurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substitutedwith 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzyl substituted with 0-1R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹,NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to S_(f);

[0637] k is 0 or 1;

[0638] S_(f) is a surfactant which is a lipid or a compound of theformula:

[0639] A⁹ is OR²⁷;

[0640] A¹⁰ is OR²⁷;

[0641] R²⁷ is C(═O)C₁₋₁₅ alkyl;

[0642] E¹ is C₁₋₄ alkylene substituted with 1-3 R²⁸;

[0643] R²⁸ is independently selected at each occurrence from the group:R³⁰, —PO₃H-R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —CH₂OR²⁹, —OR²⁹, and C₁-C₅alkyl;

[0644] R²⁹ is independently selected at each occurrence from the group:R³⁰, H, C₁-C₆ alkyl, phenyl, and benzyl;

[0645] R³⁰ is a bond to L_(n);

[0646] and a pharmaceutically acceptable salt thereof.

[0647] [41] In another more preferred embodiment, the present inventionprovides a novel ultrasound contrast agent composition, comprising:

[0648] (a) a compound of claim 39, comprising: an quinolone that bindsto the integrin α_(v)β₃, a surfactant and a linking group between thequinolone and the surfactant;

[0649] (b) a parenterally acceptable carrier; and,

[0650] (c) an echogenic gas.

[0651] [42] In another more preferred embodiment, the present inventionprovides a novel ultrasound contrast agent composition, furthercomprising: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid,1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, andN-(methoxypolyethylene glycol 5000carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.

[0652] [43] In another more preferred embodiment, the echogenic gas is aC₂₋₅ perfluorocarbon.

[0653] [44] In another preferred embodiment, the present inventionprovides a method of imaging cancer in a patient comprising: (1)administering, by injection or infusion, a ultrasound contrast agentcomposition of claim 41 to a patient; and (2) imaging the patient usingsonography.

[0654] [45] In another preferred embodiment, the present inventionprovides a method of imaging formation of new blood vessels in a patientcomprising: (1) administering, by injection or infusion, a ultrasoundcontrast agent composition of of claim 41 to a patient; (2) imaging thearea of the patient wherein the desired formation of new blood vesselsis located.

[0655] [46] In another preferred embodiment, the present inventionprovides a method of imaging therapeutic angiogenesis in a patientcomprising: (1) administering, by injection or infusion, an ultrasoundcontrast agent composition of claim 41 to a patient; (2) imaging thearea of the patient wherein the desired formation of new blood vesselsis located.

[0656] [47] In another preferred embodiment, the present inventionprovides a method of imaging atherosclerosis in a patient comprising:(1) administering, by injection or infusion, an ultrasound contrastagent composition of claim 41 to a patient; (2) imaging the area of thepatient wherein the atherosclerosis is located.

[0657] [48] In another preferred embodiment, the present inventionprovides a method of imaging restenosis in a patient comprising: (1)administering, by injection or infusion, an ultrasound contrast agentcomposition of claim 41 to a patient; (2) imaging the area of thepatient wherein the restenosis is located.

[0658] [49] In another preferred embodiment, the present inventionprovides a method of imaging cardiac ischemia in a patient comprising:(1) administering, by injection or infusion, an ultrasound contrastagent composition of claim 41 to a patient; (2) imaging the area of themyocardium wherein the ischemic region is located.

[0659] [50] In another preferred embodiment, the present inventionprovides a method of imaging myocardial reperfusion injury in a patientcomprising: (1) administering, by injection or infusion, an ultrasoundcontrast agent composition of claim 41 to a patient; (2) imaging thearea of myocardium wherein the reperfusion injury is located.

[0660] [51] In another preferred embodiment, the present inventionprovides a novel therapeutic radiopharmaceutical composition,comprising:

[0661] (a) a therapeutic radiopharmaceutical of claim 19; and,

[0662] (b) a parenterally acceptable carrier.

[0663] [52] In another preferred embodiment, the present inventionprovides a novel diagnostic pharmaceutical composition, comprising:

[0664] (a) a diagnostic radiopharmaceutical, a MRI contrast agent, or aX-ray contrast agent of claim 11; and,

[0665] (b) a parenterally acceptable carrier.

[0666] [53] In another preferred embodiment, the present inventionprovides a method of treating restenosis in a patient comprising:administering to a patient, either systemically or locally, atherapeutic radiopharmaceutical of claim 19 capable of localizing in therestenotic area and delivering an effective dose of radiation.

[0667] [54] In another preferred embodiment, the present inventionprovides a method of imaging atherosclerosis in a patient comprising:(1) administering a diagnostic radiopharmaceutical, a MRI contrastagent, or a X-ray contrast agent of claim 11 to a patient by injectionor infusion; (2) imaging the area of the patient wherein theatherosclerosis is located.

[0668] [55] In another preferred embodiment, the present inventionprovides a method of imaging restenosis in a patient comprising: (1)administering a diagnostic radiopharmaceutical, a MRI contrast agent, ora X-ray contrast agent of claim 11 to a patient by injection orinfusion; (2) imaging the area of the patient wherein the restenosis islocated.

[0669] [56] In another preferred embodiment, the present inventionprovides a method of imaging cardiac ischemia in a patient comprising:(1) administering a diagnostic radiopharmaceutical, a MRI contrastagent, or a X-ray contrast agent of claim 11 to a patient by injectionor infusion; (2) imaging the area of the myocardium wherein the ischemicregion is located.

[0670] [57] In another preferred embodiment, the present inventionprovides a method of imaging myocardial reperfusion injury in a patientcomprising: (1) administering a diagnostic radiopharmaceutical, a MRIcontrast agent, or a X-ray contrast agent of claim 11 to a patient byinjection or infusion; (2) imaging the area of myocardium wherein thereperfusion injury is located.

[0671] Another aspect of the present invention are diagnostic kits forthe preparation of radiopharmaceuticals useful as imaging agents forcancer. Diagnostic kits of the present invention comprise one or morevials containing the sterile, non-pyrogenic, formulation comprised of apredetermined amount of a reagent of the present invention, andoptionally other components such as one or two ancillary ligands,reducing agents, transfer ligands, buffers, lyophilization aids,stabilization aids, solubilization aids and bacteriostats. The inclusionof one or more optional components in the formulation will frequentlyimprove the ease of synthesis of the radiopharmaceutical by thepracticing end user, the ease of manufacturing the kit, the shelf-lifeof the kit, or the stability and shelf-life of the radiopharmaceutical.The inclusion of one or two ancillary ligands is required for diagnostickits comprising reagent comprising a hydrazine or hydrazone bondingmoiety. The one or more vials that contain all or part of theformulation can independently be in the form of a sterile solution or alyophilized solid.

[0672] Another aspect of the present invention contemplates a method ofimaging cancer in a patient involving: (1) synthesizing a diagnosticradiopharmaceutical of the present invention, using a reagent of thepresent invention, capable of localizing in tumors; (2) administeringsaid radiopharmaceutical to a patient by injection or infusion; (3)imaging the patient using planar or SPECT gamma scintigraphy, orpositron emission tomography.

[0673] Another aspect of the present invention contemplates a method ofimaging cancer in a patient involving: (1) administering a paramagneticmetallopharmaceutical of the present invention capable of localizing intumors to a patient by injection or infusion; and (2) imaging thepatient using magnetic resonance imaging.

[0674] Another aspect of the present invention contemplates a method ofimaging cancer in a patient involving: (1) administering a X-raycontrast agent of the present invention capable of localizing in tumorsto a patient by injection or infusion; and (2) imaging the patient usingX-ray computed tomography.

[0675] Another aspect of the present invention contemplates a method ofimaging cancer in a patient involving: (1) administering a ultrasoundcontrast agent of the present invention capable of localizing in tumorsto a patient by injection or infusion; and (2) imaging the patient usingsonography.

[0676] Another aspect of the present invention contemplates a method oftreating cancer in a patient involving: (1) administering a therapeuticradiopharmaceutical of the present invention capable of localizing intumors to a patient by injection or infusion.

Definitions

[0677] The compounds herein described may have asymmetric centers.Unless otherwise indicated, all chiral, diastereomeric and racemic formsare included in the present invention. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. It will be appreciated that compounds of thepresent invention contain asymmetrically substituted carbon atoms, andmay be isolated in optically active or racemic forms. It is well knownin the art how to prepare optically active forms, such as by resolutionof racemic forms or by synthesis from optically active startingmaterials. Two distinct isomers (cis and trans) of the peptide bond areknown to occur; both can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. The D and L-isomers of a particular amino acid are designatedherein using the conventional 3-letter abbreviation of the amino acid,as indicated by the following examples: D-Leu, or L-Leu.

[0678] When any variable occurs more than one time in any substituent orin any formula, its definition on each occurrence is independent of itsdefinition at every other occurrence. Thus, for example, if a group isshown to be substituted with 0-2 R⁵², then said group may optionally besubstituted with up to two R⁵², and R⁵² at each occurrence is selectedindependently from the defined list of possible R⁵². Also, by way ofexample, for the group —N(R⁵³)₂, each of the two R⁵³ substituents on Nis independently selected from the defined list of possible R⁵³.Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. When a bond to asubstituent is shown to cross the bond connecting two atoms in a ring,then such substituent may be bonded to any atom on the ring.

[0679] The term “nonpeptide” means preferably less than three amidebonds in the backbone core of the targeting moiety or preferably lessthan three amino acids or amino acid mimetics in the targeting moiety.

[0680] The term “metallopharmaceutical” means a pharmaceuticalcomprising a metal. The metal is the cause of the imageable signal indiagnostic applications and the source of the cytotoxic radiation inradiotherapeutic applications. Radiopharmaceuticals aremetallopharmaceuticals in which the metal is a radioisotope.

[0681] By “reagent” is meant a compound of this invention capable ofdirect transformation into a metallopharmaceutical of this invention.Reagents may be utilized directly for the preparation of themetallopharmaceuticals of this invention or may be a component in a kitof this invention.

[0682] The term “binding agent” means a metallopharmaceutical of thisinvention having affinity for and capable of binding to the vitronectinreceptor. The binding agents of this invention have Ki <lO00 nM.

[0683] By “stable compound” or “stable structure” is meant herein acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious pharmaceutical agent.

[0684] The term “substituted”, as used herein, means that one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's or group'snormal valency is not exceeded, and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced.

[0685] The term “bond”, as used herein, means either a single or doublebond.

[0686] The term “salt”, as used herein, is used as defined in the CRCHandbook of Chemistry and Physics, 65th Edition, CRC Press, Boca Raton,Fla, 1984, as any substance which yields ions, other than hydrogen orhydroxyl ions. As used herein, “pharmaceutically acceptable salts” referto derivatives of the disclosed compounds modified by making acid orbase salts. Examples of pharmaceutically acceptable salts include, butare not limited to, mineral or organic acid salts of basic residues suchas amines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

[0687] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[0688] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

[0689] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0690] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl;“cycloalkyl” or “carbocycle” is intended to include saturated andpartially unsaturated ring groups, including mono-, bi- or poly-cyclicring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and adamantyl; “bicycloalkyl” or “bicyclic” isintended to include saturated bicyclic ring groups such as[3.3.0]bicyclooctane,

[0691] [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),

[0692] [2.2.2]bicyclooctane, and so forth.

[0693] As used herein, the term “alkene” or “alkenyl” is intended toinclude hydrocarbon chains having the specified number of carbon atomsof either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl, propenyl, and the like.

[0694] As used herein, the term “alkyne” or “alkynyl” is intended toinclude hydrocarbon chains having the specified number of carbon atomsof either a straight or branched configuration and one or moreunsaturated carbon-carbon triple bonds which may occur in any stablepoint along the chain, such as propargyl, and the like.

[0695] As used herein, “aryl” or “aromatic residue” is intended to meanphenyl or naphthyl, which when substituted, the substitution can be atany position.

[0696] As used herein, the term “heterocycle” or “heterocyclic system”is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or7- to 10-membered bicyclic heterocyclic ring which is saturatedpartially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S and including any bicyclic group in whichany of the above-defined heterocyclic rings is fused to a benzene ring.The nitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. As used herein, the term “aromatic heterocyclic system”is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or7- to 10-membered bicyclic heterocyclic aromatic ring which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S. It is preferred that the total number ofS and O atoms in the aromatic heterocycle is not more than 1.

[0697] Examples of heterocycles include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,•-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl.,oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl. Preferred heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also includedare fused ring and spiro compounds containing, for example, the aboveheterocycles.

[0698] As used herein, the term “alkaryl” means an aryl group bearing analkyl group of 1-10 carbon atoms; the term “aralkyl” means an alkylgroup of 1-10 carbon atoms bearing an aryl group; the term “arylalkaryl”means an aryl group bearing an alkyl group of 1-10 carbon atoms bearingan aryl group; and the term “heterocycloalkyl” means an alkyl group of1-10 carbon atoms bearing a heterocycle.

[0699] A “polyalkylene glycol” is a polyethylene glycol, polypropyleneglycol or polybutylene glycol having a molecular weight of less thanabout 5000, terminating in either a hydroxy or alkyl ether moiety.

[0700] A “carbohydrate” is a polyhydroxy aldehyde, ketone, alcohol oracid, or derivatives thereof, including polymers thereof havingpolymeric linkages of the acetal type.

[0701] A “cyclodextrin” is a cyclic oligosaccharide. Examples ofcyclodextrins include, but are not limited to, α-cyclodextrin,hydroxyethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin,β-cyclodextrin, hydroxypropyl-β-cyclodextrin,carboxymethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin, 2,6 di-O-methyl-β-cyclodextrin,sulfated-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin,dihydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, andsulfated-cyclodextrin.

[0702] As used herein, the term “polycarboxyalkyl” means an alkyl grouphaving between two and about 100 carbon atoms and a plurality ofcarboxyl substituents; and the term “polyazaalkyl” means a linear orbranched alkyl group having between two and about 100 carbon atoms,interrupted by or substituted with a plurality of amine groups.

[0703] A “reducing agent” is a compound that reacts with a radionuclide,which is typically obtained as a relatively unreactive, high oxidationstate compound, to lower its oxidation state by transferring electron(s)to the radionuclide, thereby making it more reactive. Reducing agentsuseful in the preparation of radiopharmaceuticals and in diagnostic kitsuseful for the preparation of said radiopharmaceuticals include but arenot limited to stannous chloride, stannous fluoride, formamidinesulfinic acid, ascorbic acid, cysteine, phosphines, and cuprous orferrous salts. Other reducing agents are described in Brodack et. al.,PCT Application 94/22496, which is incorporated herein by reference.

[0704] A “transfer ligand” is a ligand that forms an intermediatecomplex with a metal ion that is stable enough to prevent unwantedside-reactions but labile enough to be converted to ametallopharmaceutical. The formation of the intermediate complex iskinetically favored while the formation of the metallopharmaceutical isthermodynamically favored. Transfer ligands useful in the preparation ofmetallopharmaceuticals and in diagnostic kits useful for the preparationof diagnostic radiopharmaceuticals include but are not limited togluconate, glucoheptonate, mannitol, glucarate,N,N,N′,N′-ethylenediaminetetraacetic acid, pyrophosphate andmethylenediphosphonate. In general, transfer ligands are comprised ofoxygen or nitrogen donor atoms.

[0705] The term “donor atom” refers to the atom directly attached to ametal by a chemical bond.

[0706] “Ancillary” or “co-ligands” are ligands that are incorporatedinto a radiopharmaceutical during its synthesis. They serve to completethe coordination sphere of the radionuclide together with the chelatoror radionuclide bonding unit of the reagent. For radiopharmaceuticalscomprised of a binary ligand system, the radionuclide coordinationsphere is composed of one or more chelators or bonding units from one ormore reagents and one or more ancillary or co-ligands, provided thatthere are a total of two types of ligands, chelators or bonding units.For example, a radiopharmaceutical comprised of one chelator or bondingunit from one reagent and two of the same ancillary or co-ligands and aradiopharmaceutical comprised of two chelators or bonding units from oneor two reagents and one ancillary or co-ligand are both considered to becomprised of binary ligand systems. For radiopharmaceuticals comprisedof a ternary ligand system, the radionuclide coordination sphere iscomposed of one or more chelators or bonding units from one or morereagents and one or more of two different types of ancillary orco-ligands, provided that there are a total of three types of ligands,chelators or bonding units. For example, a radiopharmaceutical comprisedof one chelator or bonding unit from one reagent and two differentancillary or co-ligands is considered to be comprised of a ternaryligand system.

[0707] Ancillary or co-ligands useful in the preparation ofradiopharmaceuticals and in diagnostic kits useful for the preparationof said radiopharmaceuticals are comprised of one or more oxygen,nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and telluriumdonor atoms. A ligand can be a transfer ligand in the synthesis of aradiopharmaceutical and also serve as an ancillary or co-ligand inanother radiopharmaceutical. Whether a ligand is termed a transfer orancillary or co-ligand depends on whether the ligand remains in theradionuclide coordination sphere in the radiopharmaceutical, which isdetermined by the coordination chemistry of the radionuclide and thechelator or bonding unit of the reagent or reagents.

[0708] A “chelator” or “bonding unit” is the moiety or group on areagent that binds to a metal ion through the formation of chemicalbonds with one or more donor atoms.

[0709] The term “binding site” means the site in vivo or in vitro thatbinds a biologically active molecule.

[0710] A “diagnostic kit” or “kit” comprises a collection of components,termed the formulation, in one or more vials which are used by thepracticing end user in a clinical or pharmacy setting to synthesizediagnostic radiopharmaceuticals. The kit provides all the requisitecomponents to synthesize and use the diagnostic radiopharmaceuticalexcept those that are commonly available to the practicing end user,such as water or saline for injection, a solution of the radionuclide,equipment for heating the kit during the synthesis of theradiopharmaceutical, if required, equipment necessary for administeringthe radiopharmaceutical to the patient such as syringes and shielding,and imaging equipment.

[0711] Therapeutic radiopharmaceuticals, X-ray contrast agentpharmaceuticals, ultrasound contrast agent pharmaceuticals andmetallopharmaceuticals for magnetic resonance imaging contrast areprovided to the end user in their final form in a formulation containedtypically in one vial, as either a lyophilized solid or an aqueoussolution. The end user reconstitutes the lyophilized with water orsaline and withdraws the patient dose or just withdraws the dose fromthe aqueous solution formulation as provided.

[0712] A “lyophilization aid” is a component that has favorable physicalproperties for lyophilization, such as the glass transition temperature,and is added to the formulation to improve the physical properties ofthe combination of all the components of the formulation forlyophilization.

[0713] A “stabilization aid” is a component that is added to themetallopharmaceutical or to the diagnostic kit either to stabilize themetallopharmaceutical or to prolong the shelf-life of the kit before itmust be used. Stabilization aids can be antioxidants, reducing agents orradical scavengers and can provide improved stability by reactingpreferentially with species that degrade other components or themetallopharmaceutical.

[0714] A “solubilization aid” is a component that improves thesolubility of one or more other components in the medium required forthe formulation.

[0715] A “bacteriostat” is a component that inhibits the growth ofbacteria in a formulation either during its storage before use of aftera diagnostic kit is used to synthesize a radiopharmaceutical.

[0716] The following abbreviations are used herein: Acm acetamidomethylb-Ala, beta-Ala 3-aminopropionic acid or bAla ATA2-aminothiazole-5-acetic acid or 2- aminothiazole-5-acetyl group Boct-butyloxycarbonyl CBZ, Cbz or Z Carbobenzyloxy Cit citrulline Dap2,3-diaminopropionic acid DCC dicyclohexylcarbodiimide DIEAdiisopropylethylamine DMAP 4-dimethylaminopyridine EOE ethoxyethyl HBTU2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphatehynic boc-hydrazinonicotinyl group or 2- [[[5- [carbonyl]-2-pyridinyl]hydrazono]methyl]- benzenesulfonic acid, NMeArg orMeArga-N-methyl arginine NMeAsp a-N-methyl aspartic acid NMMN-methylmorpholine OcHex O-cyclohexyl OBzl O-benzyl oSu O-succinimidylTBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3- tetramethyluroniumtetrafluoroborate THF tetrahydrofuranyl THP tetrahydropyranyl Tos tosylTr trityl

[0717] The following conventional three-letter amino acid abbreviationsare used herein; the conventional one-letter amino acid abbreviationsare NOT used herein: Ala = alanine Arg = arginine Asn = asparagine Asp =aspartic acid Cys = cysteine Gln = glutamine Glu = glutamic acid Gly =glycine His = histidine Ile = isoleucine Leu = leucine Lys = lysine Met= methionine Nle = norleucine Orn = ornithine Phe = phenylalanine Phg =phenylglycine Pro = proline Sar = sarcosine Ser = serine Thr = threonineTrp = tryptophan Tyr = tyrosine Val = valine

[0718] As used herein, the term “bubbles”, as used herein, refers tovesicles which are generally characterized by the presence of one ormore membranes or walls surrounding an internal void that is filled witha gas or precursor thereto. Exemplary bubbles include, for example,liposomes, micelles and the like.

[0719] As used herein, the term “lipid” refers to a synthetic ornaturally-occurring amphipathic compound which comprises a hydrophiliccomponent and a hydrophobic component. Lipids include, for example,fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alcholsand waxes, terpenes and steroids.

[0720] As used herein, the term “lipid composition” refers to acomposition which comprises a lipid compound. Exemplary lipidcompositions include suspensions, emulsions and vesicular compositions.

[0721] As used herein, the term “lipid formulation” refers to acomposition which comprises a lipid compound and a bioactive agent.

[0722] As used herein, the term “vesicle” refers to a spherical entitywhich is characterized by the presence of an internal void. Preferredvesicles are formulated from lipids, including the various lipidsdescribed herein. In any given vesicle, the lipids may be in the form ofa monolayer or bilayer, and the mono- or bilayer lipids may be used toform one of more mono- or bilayers. In the case of more than one mono-or bilayer, the mono- or bilayers are generally concentric. The lipidvesicles described herein include such entities commonly referred to asliposomes, micelles, bubbles, microbubbles, microspheres and the like.Thus, the lipids may be used to form a unilamellar vesicle (comprised ofone monolayer or bilayer), an oligolamellar vesicle (comprised of abouttwo or about three monolayers or bilayers) or a multilamellar vesicle(comprised of more than about three monolayers or bilayers). Theinternal void of the vesicles may be filled with a liquid, including,for example, an aqueous liquid, a gas, a gaseous precursor, and/or asolid or solute material, including, for example, a bioactive agent, asdesired.

[0723] As used herein, the term “vesicular composition” refers to acomposition which is formulate from lipids and which comprises vesicles.

[0724] As used herein, the term “vesicle formulation” refers to acomposition which comprises vesicles and a bioactive agent.

[0725] As used herein, the term “lipsomes” refers to a generallyspherical cluster or aggregate of amphipathic compounds, including lipidcompounds, typically in the form of one or more concentric layers, forexample, bilayers. They may also be referred to herein as lipidvesicles.

[0726] Angiogenesis is the process of formation of new capillary bloodvessels from existing vasculature. It is an important component of avariety of physiological processes including ovulation, embryonicdevelopment, wound repair, and collateral vascular generation in themyocardium. It is also central to a number of pathological conditionssuch as tumor growth and metastasis, diabetic retinopathy, and maculardegeneration. The process begins with the activation of existingvascular endothelial cells in response to a variety of cytokines andgrowth factors. The activated endothelial cells secrete enzymes thatdegrade the basement membrane of the vessels. The endothelial cells thenproliferate and migrate into the extracellular matrix first formingtubules and subsequently new blood vessels.

[0727] Under normal conditions, endothelial cell proliferation is a veryslow process, but it increases for a short period of time duringembryogenesis, ovulation and wound healing. This temporary increase incell turnover is governed by a combination of a number of growthstimulatory factors and growth suppressing factors. In pathologicalangiogenesis, this normal balance is disrupted resulting in continuedincreased endothelial cell proliferation. Some of the pro-angiogenicfactors that have been identified include basic fibroblast growth factor(bFGF), angiogenin, TGF-alpha, TGF-beta, and vascular endothelium growthfactor (VEGF), while interferon-alpha, interferon-beta andthrombospondin are examples of angiogenesis suppressors.

[0728] Angiogenic factors interact with endothelial cell surfacereceptors such as the receptor tyrosine kinases EGFR, FGFR, PDGFR,Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, and Axl.The receptors Flk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF andthese interactions play key roles in VEGF-induced angiogenesis. The Tiesubfamily of receptor tyrosine kinases are also expressed prominentlyduring blood vessel formation.

[0729] The proliferation and migration of endothelial cells in theextracellular matrix is mediated by interaction with a variety of celladhesion molecules. Integrins are a diverse family of heterodimeric cellsurface receptors by which endothelial cells attach to the extracellularmatrix, each other and other cells. Angiogenesis induced by bFGF orTNF-alpha depend on the agency of the integrin avb3, while angiogenesisinduced by VEGF depends on the integrin avb5 (Cheresh et. al., Science,1995, 270, 1500-2). Induction of expression of the integrins albl anda2b1 on the endothelial cell surface is another important mechanism bywhich VEGF promotes angiogenesis (Senger, et. al., Proc. Natl. Acad, SciUSA, 1997, 94, 13612-7).

[0730] The pharmaceuticals of the present invention are comprised of anon-peptide targeting moiety for the vitronectin receptor that isexpressed or upregulated in angiogenic tumor vasculature.

[0731] The ultrasound contrast agents of the present invention comprisea plurality of vitronectin receptor targeting moieties attached to orincorporated into a microbubble of a biocompatible gas, a liquidcarrier, and a surfactant microsphere, further comprising an optionallinking moiety, L_(n), between the targeting moieties and themicrobubble. In this context, the term liquid carrier means aqueoussolution and the term surfactant means any amphiphilic material whichproduces a reduction in interfacial tension in a solution. A list ofsuitable surfactants for forming surfactant microspheres is disclosed inEP0727225A2, herein incorporated by reference. The term surfactantmicrosphere includes nanospheres, liposomes, vesicles and the like. Thebiocompatible gas can be air, or a fluorocarbon, such as a C₃-C₅perfluoroalkane, which provides the difference in echogenicity and thusthe contrast in ultrasound imaging. The gas is encapsulated or containedin the microsphere to which is attached the biodirecting group,optionally via a linking group. The attachment can be covalent, ionic orby van der Waals forces. Specific examples of such contrast agentsinclude lipid encapsulated perfluorocarbons with a plurality of tumorneovasculature receptor binding peptides, polypeptides orpeptidomimetics.

[0732] X-ray contrast agents of the present invention are comprised ofone or more vitronectin receptor targeting moieties attached to one ormore X-ray absorbing or “heavy” atoms of atomic number 20 or greater,further comprising an optional linking moiety, L_(n), between thetargeting moieties and the X-ray absorbing atoms. The frequently usedheavy atom in X-ray contrast agents is iodine. Recently, X-ray contrastagents comprised of metal chelates (Wallace, R., U.S. Pat. No.5,417,959) and polychelates comprised of a plurality of metal ions(Love, D., U.S. Pat. No. 5,679,810) have been disclosed. More recently,multinuclear cluster complexes have been disclosed as X-ray contrastagents (U.S. Pat. No. 5,804,161, PCT WO91/14460, and PCT WO 92/17215).

[0733] MRI contrast agents of the present invention are comprised of oneor more vitronectin receptor targeting moieties attached to one or moreparamagnetic metal ions, further comprising an optional linking moiety,L_(n), between the targeting moieties and the paramagnetic metal ions.The paramagnetic metal ions are present in the form of metal complexesor metal oxide particles. U.S. Pat. Nos. 5,412,148, and 5,760,191,describe examples of chelators for paramagnetic metal ions for use inMRI contrast agents. U.S. Pat. No. 5,801,228, U.S. Pat. No. 5,567,411,and U.S. 5,281,704, describe examples of polychelants useful forcomplexing more than one paramagnetic metal ion for use in MRI contrastagents. U.S. Pat. No. 5,520,904, describes particulate compositionscomprised of paramagnetic metal ions for use as MRI contrast agents.

[0734] The pharmaceuticals of the present invention have the formulae,(Q)_(d)—L_(n)—(C_(h)—X), (Q)_(d)—L_(n)—(C_(h)—X¹)_(d′),(Q)_(d)—L_(n)—(X²)_(d″), and (Q)_(d)—L_(n)—(X³), wherein Q represents anon-peptide that binds to a receptor expressed in angiogenic tumorvasculature, d is 1-10, L_(n) represents an optional linking group,C_(h) represents a metal chelator or bonding moiety, X represents aradioisotope, X¹ represents paramagnetic metal ion, X² represents aparamagnetic metal ion or heavy atom containing insoluble solidparticle, d″ is 1-100, and X³ represents a surfactant microsphere of anechogenic gas. The interaction of the non-peptide recognition sequencesof the vitronectin receptor binding portion of the pharmaceuticals withthe αvβ3 receptor results in localization of the pharmaceuticals inangiogenic tumor vasculature, which express the αvβ3 receptor.

[0735] The pharmaceuticals of the present invention can be synthesizedby several approaches. One approach involves the synthesis of thetargeting non-peptide moiety, Q, and direct attachment of one or moremoieties, Q, to one or more metal chelators or bonding moieties, C_(h),or to a paramagnetic metal ion or heavy atom containing solid particle,or to an echogenic gas microbubble. Another approach involves theattachment of one or more moieties, Q, to the linking group, L_(n),which is then attached to one or more metal chelators or bondingmoieties, C_(h), or to a paramagnetic metal ion or heavy atom containingsolid particle, or to an echogenic gas microbubble. Another approachinvolves the synthesis of a non-peptide, Q, bearing a fragment of thelinking group, L_(n), one or more of which are then attached to theremainder of the linking group and then to one or more metal chelatorsor bonding moieties, C_(h), or to a paramagnetic metal ion or heavy atomcontaining solid particle, or to an echogenic gas microbubble.

[0736] The non-peptide vitronectin binding moieties, Q, optionallybearing a linking group, L_(n), or a fragment of the linking group, canbe synthesized using standard synthetic methods known to those skilledin the art. Preferred methods include but are not limited to thosemethods described below.

[0737] The attachment of linking groups, L_(n), to the non-peptides, Q;chelators or bonding units, C_(h), to the non-peptides, Q, or to thelinking groups, L_(n); and non-peptides, bearing a fragment of thelinking group to the remainder of the linking group, in combinationforming the moiety, (Q)_(d)—L_(n), and then to the moiety C_(h); can allbe performed by standard techniques. These include, but are not limitedto, amidation, esterification, alkylation, and the formation of ureas orthioureas. Procedures for performing these attachments can be found inBrinkley, M., Bioconjugate Chemistry 1992, 3(1), which is incorporatedherein by reference.

[0738] A number of methods can be used to attach the non-peptides, Q, toparamagnetic metal ion or heavy atom containing solid particles, X², byone of skill in the art of the surface modification of solid particles.In general, the targeting moiety Q or the combination (Q)_(d)L_(n) isattached to a coupling group that react with a constituent of thesurface of the solid particle. The coupling groups can be any of anumber of silanes which react with surface hydroxyl groups on the solidparticle surface, as described in co-pending U.S. patent applicationSer. No. 09/356,178, and can also include polyphosphonates,polycarboxylates, polyphosphates or mixtures thereof which couple withthe surface of the solid particles, as described in U.S. Pat. No.5,520,904.

[0739] A number of reaction schemes can be used to attach thenon-peptides, Q, to the surfactant microsphere, X³. These areillustrated in following reaction schemes where S_(f) represents asurfactant moiety that forms the surfactant microsphere.

[0740] Acylation Reaction:

S_(f)—C(═O)—Y+Q—NH₂ or→S_(f)—C(═O)—NH—Q

Q—OH or S_(f)—C(═O)—O—Q

[0741] Y is a leaving group or active ester

[0742] Disulfide Coupling:

S_(f)—SH+Q—SH→S_(f)—S—S—Q

[0743] Sulfonamide Coupling:

S_(f)—S(═O)₂—Y+Q—NH₂→S_(f)—S(═O)₂—NH—Q

[0744] Reductive Amidation:

S_(f)—CHO+Q—NH₂→S_(f)—NH—Q

[0745] In these reaction schemes, the substituents S_(f) and Q can bereversed as well.

[0746] The linking group L_(n) can serve several roles. First itprovides a spacing group between the metal chelator or bonding moiety,C_(h), the paramagnetic metal ion or heavy atom containing solidparticle, X², and the surfactant microsphere, X³, and the one or more ofthe non-peptides, Q, so as to minimize the possibility that the moietiesC_(h)—X, C_(h)—X¹, X², and X³, will interfere with the interaction ofthe recognition sequences of Q with angiogenic tumor vasculaturereceptors. The necessity of incorporating a linking group in a reagentis dependent on the identity of Q, C_(h)—X, C_(h)—X¹, X², and X³. IfC_(h)—X, C_(h)—X¹, X², and X³, cannot be attached to Q withoutsubstantially diminishing its affinity for the receptors, then a linkinggroup is used. A linking group also provides a means of independentlyattaching multiple non-peptides, Q, to one group that is attached toC_(h)—X, C_(h)—X¹, X², or X³.

[0747] The linking group also provides a means of incorporating apharmacokinetic modifier into the pharmaceuticals of the presentinvention. The pharmacokinetic modifier serves to direct thebiodistibution of the injected pharmaceutical other than by theinteraction of the targeting moieties, Q, with the vitronectin receptorsexpressed in the tumor neovasculature. A wide variety of functionalgroups can serve as pharmacokinetic modifiers, including, but notlimited to, carbohydrates, polyalkylene glycols, peptides or otherpolyamino acids, and cyclodextrins. The modifiers can be used to enhanceor decrease hydrophilicity and to enhance or decrease the rate of bloodclearance. The modifiers can also be used to direct the route ofelimination of the pharmaceuticals. Preferred pharmacokinetic modifiersare those that result in moderate to fast blood clearance and enhancedrenal excretion.

[0748] The metal chelator or bonding moiety, C_(h), is selected to formstable complexes with the metal ion chosen for the particularapplication. Chelators or bonding moieties for diagnosticradiopharmaceuticals are selected to form stable complexes with theradioisotopes that have imageable gamma ray or positron emissions, suchas ^(99m)Tc, ⁹⁵Tc, ¹¹¹In, ⁶²Cu, ⁶⁰Cu, ⁶⁴Cu, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y.

[0749] Chelators for technetium, copper and gallium isotopes areselected from diaminedithiols, monoamine-monoamidedithiols,triamide-monothiols, monoamine-diamide-monothiols, diaminedioximes, andhydrazines. The chelators are generally tetradentate with donor atomsselected from nitrogen, oxygen and sulfur. Preferred reagents arecomprised of chelators having amine nitrogen and thiol sulfur donoratoms and hydrazine bonding units. The thiol sulfur atoms and thehydrazines may bear a protecting group which can be displaced eitherprior to using the reagent to synthesize a radiopharmaceutical orpreferably in situ during the synthesis of the radiopharmaceutical.

[0750] Exemplary thiol protecting groups include those listed in Greeneand Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons,New York (1991), the disclosure of which is hereby incorporated byreference. Any thiol protecting group known in the art can be used.Examples of thiol protecting groups include, but are not limited to, thefollowing: acetamidomethyl, benzamidomethyl, 1-ethoxyethyl, benzoyl, andtriphenylmethyl.

[0751] Exemplary protecting groups for hydrazine bonding units arehydrazones which can be aldehyde or ketone hydrazones havingsubstituents selected from hydrogen, alkyl, aryl and heterocycle.Particularly preferred hydrazones are described in co-pending U.S. Ser.No. 08/476,296 the disclosure of which is herein incorporated byreference in its entirety.

[0752] The hydrazine bonding unit when bound to a metal radionuclide istermed a hydrazido, or diazenido group and serves as the point ofattachment of the radionuclide to the remainder of theradiopharmaceutical. A diazenido group can be either terminal (only oneatom of the group is bound to the radionuclide) or chelating. In orderto have a chelating diazenido group at least one other atom of the groupmust also be bound to the radionuclide. The atoms bound to the metal aretermed donor atoms.

[0753] Chelators for ¹¹¹In and ⁸⁶Y are selected from cyclic and acyclicpolyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA,alpha-(2-phenethyl)1,4,7,10-tetraazazcyclododecane-1-acetic-4,7,10-tris(methylacetic)acid, 2-benzyl-cyclohexyldiethylenetriaminepentaaceticacid, 2-benzyl-6-methyl-DTPA, and6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.Procedures for synthesizing these chelators that are not commerciallyavailable can be found in Brechbiel, M. and Gansow, O., J. Chem. Soc.Perkin Trans. 1992, 1, 1175; Brechbiel, M. and Gansow, O., BioconjugateChem. 1991, 2, 187; Deshpande, S., et. al., J. Nucl. Med. 1990, 31, 473;Kruper, J., U.S. Pat. No. 5,064,956, and Toner, J., U.S. Pat. No.4,859,777, the disclosures of which are hereby incorporated by referencein their entirety.

[0754] The coordination sphere of metal ion includes all the ligands orgroups bound to the metal. For a transition metal radionuclide to bestable it typically has a coordination number (number of donor atoms)comprised of an integer greater than or equal to 4 and less than orequal to 8; that is there are 4 to 8 atoms bound to the metal and it issaid to have a complete coordination sphere. The requisite coordinationnumber for a stable radionuclide complex is determined by the identityof the radionuclide, its oxidation state, and the type of donor atoms.If the chelator or bonding unit does not provide all of the atomsnecessary to stabilize the metal radionuclide by completing itscoordination sphere, the coordination sphere is completed by donor atomsfrom other ligands, termed ancillary or co-ligands, which can also beeither terminal or chelating.

[0755] A large number of ligands can serve as ancillary or co-ligands,the choice of which is determined by a variety of considerations such asthe ease of synthesis of the radiopharmaceutical, the chemical andphysical properties of the ancillary ligand, the rate of formation, theyield, and the number of isomeric forms of the resultingradiopharmaceuticals, the ability to administer said ancillary orco-ligand to a patient without adverse physiological consequences tosaid patient, and the compatibility of the ligand in a lyophilized kitformulation. The charge and lipophilicity of the ancillary ligand willeffect the charge and lipophilicity of the radiopharmaceuticals. Forexample, the use of 4,5-dihydroxy-1,3-benzene disulfonate results inradiopharmaceuticals with an additional two anionic groups because thesulfonate groups will be anionic under physiological conditions. The useof N-alkyl substituted 3,4-hydroxypyridinones results inradiopharmaceuticals with varying degrees of lipophilicity depending onthe size of the alkyl substituents.

[0756] Preferred technetium radiopharmaceuticals of the presentinvention are comprised of a hydrazido or diazenido bonding unit and anancillary ligand, A_(L1), or a bonding unit and two types of ancillaryA_(L1) and A_(L2), or a tetradentate chelator comprised of two nitrogenand two sulfur atoms. Ancillary ligands A_(L1) are comprised of two ormore hard donor atoms such as oxygen and amine nitrogen (sp³hybridized). The donor atoms occupy at least two of the sites in thecoordination sphere of the radionuclide metal; the ancillary ligandA_(L1) serves as one of the three ligands in the ternary ligand system.Examples of ancillary ligands A_(L1) include but are not limited todioxygen ligands and functionalized aminocarboxylates. A large number ofsuch ligands are available from commercial sources.

[0757] Ancillary dioxygen ligands include ligands that coordinate to themetal ion through at least two oxygen donor atoms. Examples include butare not limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate,lactate, tartrate, mannitol, glucarate, maltol, Kojic acid,2,2-bis(hydroxymethyl)propionic acid, 4,5-dihydroxy-1,3-benzenedisulfonate, or substituted or unsubstituted 1,2 or 3,4hydroxypyridinones. (The names for the ligands in these examples referto either the protonated or non-protonated forms of the ligands.)

[0758] Functionalized aminocarboxylates include ligands that have acombination of amine nitrogen and oxygen donor atoms. Examples includebut are not limited to: iminodiacetic acid, 2,3-diaminopropionic acid,nitrilotriacetic acid, N,N′-ethylenediamine diacetic acid,N,N,N′-ethylenediamine triacetic acid, hydroxyethylethylenediaminetriacetic acid, and N,N′-ethylenediamine bis-hydroxyphenylglycine. (Thenames for the ligands in these examples refer to either the protonatedor non-protonated forms of the ligands.)

[0759] A series of functionalized aminocarboxylates are disclosed byBridger et. al. in U.S. Pat. No. 5,350,837, herein incorporated byreference, that result in improved rates of formation of technetiumlabeled hydrazino modified proteins. We have determined that certain ofthese aminocarboxylates result in improved yields of theradiopharmaceuticals of the present invention. The preferred ancillaryligands A_(L1) functionalized aminocarboxylates that are derivatives ofglycine; the most preferred is tricine(tris(hydroxymethyl)methylglycine).

[0760] The most preferred technetium radiopharmaceuticals of the presentinvention are comprised of a hydrazido or diazenido bonding unit and twotypes of ancillary designated A_(L1) and A_(L2), or a diaminedithiolchelator. The second type of ancillary ligands A_(L2) are comprised ofone or more soft donor atoms selected from the group: phosphinephosphorus, arsine arsenic, imine nitrogen (sp² hybridized), sulfur (sp²hybridized) and carbon (sp hybridized); atoms which have p-acidcharacter. Ligands A_(L2) can be monodentate, bidentate or tridentate,the denticity is defined by the number of donor atoms in the ligand. Oneof the two donor atoms in a bidentate ligand and one of the three donoratoms in a tridentate ligand must be a soft donor atom. We havedisclosed in co-pending U.S. Ser. No. 08/415,908, and U.S. Ser. No.60/013,360 and Ser. No. 08/646,886, the disclosures of which are hereinincorporated by reference in their entirety, that radiopharmaceuticalscomprised of one or more ancillary or co-ligands A_(L2) are more stablecompared to radiopharmaceuticals that are not comprised of one or moreancillary ligands, A_(L2); that is, they have a minimal number ofisomeric forms, the relative ratios of which do not change significantlywith time, and that remain substantially intact upon dilution.

[0761] The ligands A_(L2) that are comprised of phosphine or arsinedonor atoms are trisubstituted phosphines, trisubstituted arsines,tetrasubstituted diphosphines and tetrasubstituted diarsines. Theligands A_(L2) that are comprised of imine nitrogen are unsaturated oraromatic nitrogen-containing, 5 or 6-membered heterocycles. The ligandsthat are comprised of sulfur (sp² hybridized) donor atoms arethiocarbonyls, comprised of the moiety C═S. The ligands comprised ofcarbon (sp hybridized) donor atoms are isonitriles, comprised of themoiety CNR, where R is an organic radical. A large number of suchligands are available from commercial sources. Isonitriles can besynthesized as described in European Patent 0107734 and in U.S. Pat. No.4,988,827, herein incorporated by reference.

[0762] Preferred ancillary ligands A_(L2) are trisubstituted phosphinesand unsaturated or aromatic 5 or 6 membered heterocycles. The mostpreferred ancillary ligands A_(L2) are trisubstituted phosphines andunsaturated 5 membered heterocycles.

[0763] The ancillary ligands A_(L2) may be substituted with alkyl, aryl,alkoxy, heterocycle, aralkyl, alkaryl and arylalkaryl groups and may ormay not bear functional groups comprised of heteroatoms such as oxygen,nitrogen, phosphorus or sulfur. Examples of such functional groupsinclude but are not limited to: hydroxyl, carboxyl, carboxamide, nitro,ether, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate, andphosphonamide. The functional groups may be chosen to alter thelipophilicity and water solubility of the ligands which may affect thebiological properties of the radiopharmaceuticals, such as altering thedistribution into non-target tissues, cells or fluids, and the mechanismand rate of elimination from the body.

[0764] Chelators or bonding moieties for therapeuticradiopharmaceuticals are selected to form stable complexes with theradioisotopes that have alpha particle, beta particle, Auger orCoster-Kronig electron emissions, such as ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho,¹⁷⁷Lu, 149Pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴OLa, ¹⁹⁸AU, ¹⁹⁹Au,¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir. Chelators forrhenium, copper, palladium, platinum, iridium, rhodium, silver and goldisotopes are selected from diaminedithiols, monoamine-monoamidedithiols,triamide-monothiols, monoamine-diamide-monothiols, diaminedioximes, andhydrazines. Chelators for yttrium, bismuth, and the lanthanide isotopesare selected from cyclic and acyclic polyaminocarboxylates such as DTPA,DOTA, DO3A, 2-benzyl-DOTA,alpha-(2-phenethyl)1,4,7,10-tetraazacyclododecane-1-acetic-4,7,10-tris(methylacetic)acid,2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid,2-benzyl-6-methyl-DTPA, and6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.

[0765] Chelators for magnetic resonance imaging contrast agents areselected to form stable complexes with paramagnetic metal ions, such asGd(III), Dy(III), Fe(III), and Mn(II), are selected from cyclic andacyclic polyaminocarboxylates such as DTPA, DOTA, DO3A, 2-benzyl-DOTA,alpha-(2-phenethyl)1,4,7,10-tetraazacyclododecane-1-acetic-4,7,10-tris(methylacetic)acid,2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid,2-benzyl-6-methyl-DTPA, and6,6″-bis[N,N,N″,N″-tetra(carboxymethyl)aminomethyl)-4′-(3-amino-4-methoxyphenyl)-2,2′:6′,2″-terpyridine.

[0766] The technetium and rhenium radiopharmaceuticals of the presentinvention comprised of a hydrazido or diazenido bonding unit can beeasily prepared by admixing a salt of a radionuclide, a reagent of thepresent invention, an ancillary ligand A_(L1), an ancillary ligandA_(L2), and a reducing agent, in an aqueous solution at temperaturesfrom 0 to 100° C. The technetium and rhenium radiopharmaceuticals of thepresent invention comprised of a tetradentate chelator having twonitrogen and two sulfur atoms can be easily prepared by admixing a saltof a radionuclide, a reagent of the present invention, and a reducingagent, in an aqueous solution at temperatures from 0 to 100° C.

[0767] When the bonding unit in the reagent of the present invention ispresent as a hydrazone group, then it must first be converted to ahydrazine, which may or may not be protonated, prior to complexationwith the metal radionuclide. The conversion of the hydrazone group tothe hydrazine can occur either prior to reaction with the radionuclide,in which case the radionuclide and the ancillary or co-ligand or ligandsare combined not with the reagent but with a hydrolyzed form of thereagent bearing the chelator or bonding unit, or in the presence of theradionuclide in which case the reagent itself is combined with theradionuclide and the ancillary or co-ligand or ligands. In the lattercase, the pH of the reaction mixture must be neutral or acidic.

[0768] Alternatively, the radiopharmaceuticals of the present inventioncomprised of a hydrazido or diazenido bonding unit can be prepared byfirst admixing a salt of a radionuclide, an ancillary ligand A_(L1), anda reducing agent in an aqueous solution at temperatures from 0 to 100°C. to form an intermediate radionuclide complex with the ancillaryligand A_(L1) then adding a reagent of the present invention and anancillary ligand A_(L2) and reacting further at temperatures from 0 to100° C.

[0769] Alternatively, the radiopharmaceuticals of the present inventioncomprised of a hydrazido or diazenido bonding unit can be prepared byfirst admixing a salt of a radionuclide, an ancillary ligand A_(L1), areagent of the present invention, and a reducing agent in an aqueoussolution at temperatures from 0 to 100° C. to form an intermediateradionuclide complex, and then adding an ancillary ligand A_(L2) andreacting further at temperatures from 0 to 100° C.

[0770] The technetium and rhenium radionuclides are preferably in thechemical form of pertechnetate or perrhenate and a pharmaceuticallyacceptable cation. The pertechnetate salt form is preferably sodiumpertechnetate such as obtained from commercial Tc-99m generators. Theamount of pertechnetate used to prepare the radiopharmaceuticals of thepresent invention can range from 0.1 mCi to 1 Ci, or more preferablyfrom 1 to 200 mCi.

[0771] The amount of the reagent of the present invention used toprepare the technetium and rhenium radiopharmaceuticals of the presentinvention can range from 0.01 μg to 10 mg, or more preferably from 0.5μg to 200 μg. The amount used will be dictated by the amounts of theother reactants and the identity of the radiopharmaceuticals of thepresent invention to be prepared.

[0772] The amounts of the ancillary ligands A_(L1) used can range from0.1 mg to 1 g, or more preferably from 1 mg to 100 mg. The exact amountfor a particular radiopharmaceutical is a function of identity of theradiopharmaceuticals of the present invention to be prepared, theprocedure used and the amounts and identities of the other reactants.Too large an amount of A_(L1) will result in the formation ofby-products comprised of technetium labeled A_(L1) without abiologically active molecule or by-products comprised of technetiumlabeled biologically active molecules with the ancillary ligand A_(L1)but without the ancillary ligand A_(L2). Too small an amount of A_(L1)will result in other by-products such as technetium labeled biologicallyactive molecules with the ancillary ligand A_(L2) but without theancillary ligand A_(L1), or reduced hydrolyzed technetium, or technetiumcolloid.

[0773] The amounts of the ancillary ligands A_(L2) used can range from0.001 mg to 1 g, or more preferably from 0.01 mg to 10 mg. The exactamount for a particular radiopharmaceutical is a function of theidentity of the radiopharmaceuticals of the present invention to beprepared, the procedure used and the amounts and identities of the otherreactants. Too large an amount of A_(L2) will result in the formation ofby-products comprised of technetium labeled A_(L2) without abiologically active molecule or by-products comprised of technetiumlabeled biologically active molecules with the ancillary ligand A_(L2)but without the ancillary ligand A_(L1). If the reagent bears one ormore substituents that are comprised of a soft donor atom, as definedabove, at least a ten-fold molar excess of the ancillary ligand A_(L2)to the reagent of formula 2 is required to prevent the substituent frominterfering with the coordination of the ancillary ligand A_(L2) to themetal radionuclide.

[0774] Suitable reducing agents for the synthesis of theradiopharmaceuticals of the present invention include stannous salts,dithionite or bisulfite salts, borohydride salts, andformamidinesulfinic acid, wherein the salts are of any pharmaceuticallyacceptable form. The preferred reducing agent is a stannous salt. Theamount of a reducing agent used can range from 0.001 mg to 10 mg, ormore preferably from 0.005 mg to 1 mg.

[0775] The specific structure of a radiopharmaceutical of the presentinvention comprised of a hydrazido or diazenido bonding unit will dependon the identity of the reagent of the present invention used, theidentity of any ancillary ligand A_(L1), the identity of any ancillaryligand A_(L2), and the identity of the radionuclide.Radiopharmaceuticals comprised of a hydrazido or diazenido bonding unitsynthesized using concentrations of reagents of <100 μg/mL, will becomprised of one hydrazido or diazenido group. Those synthesizedusing >1 mg/mL concentrations will be comprised of two hydrazido ordiazenido groups from two reagent molecules. For most applications, onlya limited amount of the biologically active molecule can be injected andnot result in undesired side-effects, such as chemical toxicity,interference with a biological process or an altered biodistribution ofthe radiopharmaceutical. Therefore, the radiopharmaceuticals whichrequire higher concentrations of the reagents comprised in part of thebiologically active molecule, will have to be diluted or purified aftersynthesis to avoid such side-effects.

[0776] The identities and amounts used of the ancillary ligands A_(L1)and A_(L2) will determine the values of the variables y and z. Thevalues of y and z can independently be an integer from 1 to 2. Incombination, the values of y and z will result in a technetiumcoordination sphere that is made up of at least five and no more thanseven donor atoms. For monodentate ancillary ligands A_(L2), z can be aninteger from 1 to 2; for bidentate or tridentate ancillary ligandsA_(L2), Z is 1. The preferred combination for monodentate ligands is yequal to 1 or 2 and z equal to 1. The preferred combination forbidentate or tridentate ligands is y equal to 1 and z equal to 1.

[0777] The indium, copper, gallium, silver, palladium, rhodium, gold,platinum, bismuth, yttrium and lanthanide radiopharmaceuticals of thepresent invention can be easily prepared by admixing a salt of aradionuclide and a reagent of the present invention, in an aqueoussolution at temperatures from 0 to 100° C. These radionuclides aretypically obtained as a dilute aqueous solution in a mineral acid, suchas hydrochloric, nitric or sulfuric acid. The radionuclides are combinedwith from one to about one thousand equivalents of the reagents of thepresent invention dissolved in aqueous solution. A buffer is typicallyused to maintain the pH of the reaction mixture between 3 and 10.

[0778] The gadolinium, dysprosium, iron and manganesemetallopharmaceuticals of the present invention can be easily preparedby admixing a salt of the paramagnetic metal ion and a reagent of thepresent invention, in an aqueous solution at temperatures from 0 to 100°C. These paramagnetic metal ions are typically obtained as a diluteaqueous solution in a mineral acid, such as hydrochloric, nitric orsulfuric acid. The paramagnetic metal ions are combined with from one toabout one thousand equivalents of the reagents of the present inventiondissolved in aqueous solution. A buffer is typically used to maintainthe pH of the reaction mixture between 3 and 10.

[0779] The total time of preparation will vary depending on the identityof the metal ion, the identities and amounts of the reactants and theprocedure used for the preparation. The preparations may be complete,resulting in >80% yield of the radiopharmaceutical, in 1 minute or mayrequire more time. If higher purity metallopharmaceuticals are needed ordesired, the products can be purified by any of a number of techniqueswell known to those skilled in the art such as liquid chromatography,solid phase extraction, solvent extraction, dialysis or ultrafiltration.

[0780] Buffers useful in the preparation of metallopharmaceuticals andin diagnostic kits useful for the preparation of saidradiopharmaceuticals include but are not limited to phosphate, citrate,sulfosalicylate, and acetate. A more complete list can be found in theUnited States Pharmacopeia.

[0781] Lyophilization aids useful in the preparation of diagnostic kitsuseful for the preparation of radiopharmaceuticals include but are notlimited to mannitol, lactose, sorbitol, dextran, Ficoll, andpolyvinylpyrrolidine(PVP).

[0782] Stabilization aids useful in the preparation ofmetallopharmaceuticals and in diagnostic kits useful for the preparationof radiopharmaceuticals include but are not limited to ascorbic acid,cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite,gentisic acid, and inositol.

[0783] Solubilization aids useful in the preparation ofmetallopharmaceuticals and in diagnostic kits useful for the preparationof radiopharmaceuticals include but are not limited to ethanol,glycerin, polyethylene glycol, propylene glycol, polyoxyethylenesorbitan monooleate, sorbitan monoloeate, polysorbates,poly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymers(Pluronics) and lecithin. Preferred solubilizing aids are polyethyleneglycol, and Pluronics.

[0784] Bacteriostats useful in the preparation of metallopharmaceuticalsand in diagnostic kits useful for the preparation ofradiopharmaceuticals include but are not limited to benzyl alcohol,benzalkonium chloride, chlorbutanol, and methyl, propyl or butylparaben.

[0785] A component in a diagnostic kit can also serve more than onefunction. A reducing agent can also serve as a stabilization aid, abuffer can also serve as a transfer ligand, a lyophilization aid canalso serve as a transfer, ancillary or co-ligand and so forth.

[0786] The diagnostic radiopharmaceuticals are administered byintravenous injection, usually in saline solution, at a dose of 1 to 100mCi per 70 kg body weight, or preferably at a dose of 5 to 50 mCi.Imaging is performed using known procedures.

[0787] The therapeutic radiopharmaceuticals are administered byintravenous injection, usually in saline solution, at a dose of 0.1 to100 mCi per 70 kg body weight, or preferably at a dose of 0.5 to 5 mCiper 70 kg body weight.

[0788] The magnetic resonance imaging contrast agents of the presentinvention may be used in a similar manner as other MRI agents asdescribed in U.S. Pat. No. 5,155,215; U.S. Pat. No. 5,087,440;Margerstadt et al., Magn. Reson. Med., 1986, 3, 808; Runge et al.,Radiology, 1988, 166, 835; and Bousquet et al., Radiology, 1988, 166,693. Generally, sterile aqueous solutions of the contrast agents areadministered to a patient intravenously in dosages ranging from 0.01 to1.0 mmoles per kg body weight.

[0789] For use as X-ray contrast agents, the compositions of the presentinvention should generally have a heavy atom concentration of 1 mM to 5M, preferably 0.1 M to 2 M. Dosages, administered by intravenousinjection, will typically range from 0.5 mmol/kg to 1.5 mmol/kg,preferably 0.8 mmol/kg to 1.2 mmol/kg. Imaging is performed using knowntechniques, preferably X-ray computed tomography.

[0790] The ultrasound contrast agents of the present invention areadministered by intravenous injection in an amount of 10 to 30 μL of theechogenic gas per kg body weight or by infusion at a rate ofapproximately 3 μL/kg/min. Imaging is performed using known techniquesof sonography.

[0791] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments which aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES

[0792] Representative materials and methods that may be used inpreparing the compounds of the invention are described further below.1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)hydroquinoline-3-carboxylicacid, ethyl 7-bromo-4-oxohydroquinoline-3-carboxylate,1-(triphenylmethyl)imidazole-2-ylamine, and methyl3-amino-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoatehydrochloride were prepared as described in PCT WO 98/23608.Boc-L-cysteic acid, Boc-L-cysteic acid N-hydroxyphenyl ester, andBoc-L-cysteic acid p-nitrophenyl ester were prepared as described inLiebigs Ann. Chem. 1979, 776-783.Benzotriazole-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate(PYBOP) was purchased from Novabiochem.(tert-butoxy)-N-(3-bromopropyl)formamide and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid were prepared as described in PCT WO 96/40637. All other chemicalsand solvents (reagent grade) were used as supplied from the vendorscited without further purification. t-Butyloxycarbonyl (Boc) amino acidsand other starting amino acids may be obtained commercially from BachemInc., Bachem Biosciences Inc. (Philadelphia, Pa.), Advanced ChemTech(Louisville, Ky.), Peninsula Laboratories (Belmont, Calif.), or Sigma(St. Louis, Mo.). 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU) and TBTU were purchased from AdvancedChemTech. N-methylmorpholine (NMM), m-cresol, D-2-aminobutyric acid(Abu), trimethylacetylchloride, diisopropylethylamine (DIEA),1,2,4-triazole, stannous chloride dihydrate,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),triethylsilane (Et₃SiH) and tris(3-sulfonatophenyl)phosphine trisodiumsalt (TPPTS) were purchased from Aldrich Chemical Company.Bis(3-sulfonatophenyl)phenylphosphine disodium salt (TPPDS) was preparedby the published procedure (Kuntz, E., U.S. Pat. No. 4,248,802).(3-Sulfonatophenyl)diphenylphosphine monosodium salt (TPPMS)waspurchased from TCI America, Inc. Tricine was obtained from ResearchOrganics, Inc. Technetium-99m-pertechnetate (^(99m)TcO₄-) was obtainedfrom a DuPont Pharma ⁹⁹Mo/^(99m)Tc Technelite® generator.In-111-chloride (Indichlor®) was obtained from Amersham Medi-Physics,Inc. Sm-153-chloride and Lutetium-177-chloride were obtained from theUniversity of Missouri Research Reactor (MURR). Yttrium-90 chloride wasobtained from the Pacific Northwest Research Laboratories.Dimethylformamide (DMF), ethyl acetate, chloroform (CHCl₃), methanol(MeOH), pyridine and hydrochloric acid (HCl) were obtained from Baker.Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), trifluoroaceticacid (TFA), ethyl ether, triethylamine, acetone, and magnesium sulfatewere commercially obtained. Absolute ethanol was obtained from QuantumChemical Corporation.

[0793] Synthesis of Boc-Glu-(OTFP)-OTFP

[0794] To a solution of Boc-Glu-OH (28.9 g, 117 mmol) in DMF (500 mL) atroom temperature, and under nitrogen, was added a solution of2,3,5,6-tetrafluorophenol (48.2 g, 290 mmol) in DMF (50 mL). Afterstirring for 10 min. EDC (55.6 g, 290 mmol) was added and the reactionmixture was stirred for about 96 h. The volatiles were removed in vacuoand the residue was triturated in 0.1 N HCl (750 mL). To this mixturewas added ethyl acetate (600 mL), the layers separated. The aqueouslayer was extracted with ethyl acetate (3×˜500 mL), and all the ethylacetate fractions were combined, washed with water (300 μmL) and brine(300 mL), dried (MgSO₄), and concentrated to give a tan solid (62 g).The tan solid was washed with acetonitrile to give the title compound(45.5 g, 73%) in purified form.

[0795] ESMS: Calculated for C₂₂H₁₇F₈NO₆, 543.09; found, 566.0 [M+Na]⁺¹.

Example 12-(((4-(4-(((3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt

[0796] PartA—N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(phenylmethoxy)formamide

[0797] A solution of 4,7,10-trioxa-1,13-tridecanediamine (158 mL, 0.72mol), TEA (16.7 mL, 0.12 mol), and MeOH (300 mL) in peroxide-free THF(1,000 mL) was placed in a 3 liter 3-neck flask fitted with a mechanicalstirrer, a thermometer, and an addition funnel with nitrogen line. Theaddition funnel was charged with a solution of benzyl chloroformate(17.1 mL, 0.12 mol) in peroxide-free THF (1,000 mL). The contents of theflask were cooled below 5° C. The contents of the addition funnel wereadded to the flask with rapid stirring over 4 h while keeping thetemperature below 5° C. The solution was stirred an additional 30 minand concentrated to give a thick syrup. This syrup was taken up insaturated NaCl (1800 mL) and 10% Na₂CO₃ (200 mL) and extracted withether (3×1,000 mL). The combined ether extracts were washed withsaturated NaCl (500 μL), dried (MgSO₄), and concentrated to give a paleyellow oil (36.74 g). Flash chromatography on a 7×29 cm silica gelcolumn (DCM/MeOH/TEA, 20/15/0.5) gave the title compound as a colorlesssyrup (19.14 g, 45%). ¹H NMR (CDCl₃): 7.33-7.25 (m, 5H), 5.59 (s, 1H),5.06 (s, 2H), 3.62-3.45 (m, 12H), 3.32-3.25 (m, 2H), 2.74 (t, J=6.7 Hz,2H), 1.75 (pentet, J=6.0 Hz, 2H), 1.67 (pentet, J=6.4 Hz, 2H), 1.33 (s,2H); MS: m/e 355.4 [M+H]; High Resolution MS: Calcd for C₁₈H₃₁N₂O₅[M+H]: 355.2233, Found: 355.2222.

[0798] Part B—Methyl3-((tert-Butoxy)carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoate

[0799] Biphenyl-4,4′-disulfonyl chloride (2.64 g, 7.5 mmol, freshlyrecrystallized from CHCl₃) and DCM (200 mL) were placed in a 500 mL3-neck flask fitted with a thermometer, an addition funnel, and anitrogen line. The addition funnel was charged with a solution ofN-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(phenylmethoxy)formamide(1.77 g, 5.0 mmol) and DIEA (0.87 mL, 5.0 mmol) in DCM (40 mL). Thecontents of the flask were cooled below 5° C. The contents of theaddition funnel were added to the flask with rapid stirring over 3 hwhile keeping the temperature of the flask below 5° C. The additionfunnel was charged with a solution of N-β-Boc-L-α,β,-diaminopropionicacid methyl ester hydrochloride (2.55 g, 10 mmol) and DIEA (3.8 mL, 22mmol) in DCM (25 mL). This solution was added to the flask with stirringat 5° C. over 15 min, and stirred at ambient temperatures for anadditional 20 h. The reaction solution was washed consecutively with 0.1N HCl (100 mL) and water (2×100 mL), dried (MgSO₄), and concentrated togive a viscous oil (5.79 g). Flash chromatography on a 5×21 cm silicagel column (85/15 EtOAc/hexanes, followed by 100% EtOAc) gave acolorless amorphous solid. Recrystallization from toluene (85 mL) gavethe title compound as a colorless solid (2.52 g, 59%). MP: 104.5-106.5°C.; ¹H NMR (CDCl₃): 8.00-7.90 (m, 4H), 7.72-7.64 (m, 4H), 7.46-7.24 (m,5H), 5.96-5.88 (m, 1H), 5.86-5.73 (m, 1H), 5.41 (s, 1H), 5.16-5.00 (m,3H), 4.15-4.02 (m, 1H), 3.68-3.39 (m, 17H), 3.34-3.22 (m, 2H), 3.13-3.03(m, 2H), 1.80-1.62 (m, 4H), 1.39 (s, 9H); ¹³C NMR (CDCl₃): 170.2, 156.5,156.1, 143.9, 143.0, 140.4, 139.4, 136.7, 128.4, 128.1, 128.0, 127.9,127.9, 127.8, 127.3, 80.1, 70.6, 70.5, 70.2, 70.1, 70.0, 69.6, 66.5,56.1, 52.9, 43.2, 42.4, 39.3, 29.4, 28.5, 28.2; MS: m/e 868.3 [M+NH₄];High Resolution MS: Calcd for C₃₉H₅₅N₄O₁₃S₂ [M+H]: 851.3207, Found:851.3226.

[0800] Part C—Methyl3-((1-Methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoate

[0801] The product of Part B, above (748 mg, 0.88 mmol) was dissolved in25/75 TFA/DCM (15 mL) and allowed to stand at ambient temperatures undernitrogen for 15 min. The TFA was removed under vacuum and the resultingamber oil was taken up in 50/50 ACN/water (50 mL), and treated portionwise with Bio-Rad AG-3-X4A resin, hydroxide form, to raise the pH from 2to 6. The resin was removed by filtration and the filtrate waslyophilized to give a sticky pale yellow foam.

[0802] In a separate flask, 1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)hydroquinoline-3-carboxylic acid (432 mg,0.80 mmol), TEA (0.33 mL), and HBTU (364 mg, 0.96 mmol) were dissolvedin anhydrous DMF (25 mL). The resulting solution was stirred at ambienttemperatures under a nitrogen atmosphere for 10 min and combined with asolution of the yellow foam in anhydrous DMF (15 mL). The DMF wasremoved under vacuum after 18 h to give a viscous yellow oil. This oilwas taken up in EtOAc (175 mL), washed consecutively with water (25 mL),saturated NaHCO₃ (50 mL), and saturated NaCl (25 mL), dried (MgSO₄), andconcentrated to give a viscous yellow oil. Purification by flashchromatography on a 7×25 cm silica gel column using a CHCl₃/EtOAc/MeOHstep gradient (47/47/6, 46/46/8, 60/30/10) gave the title compound as apale yellow solid (510 mg, 50%). MP: 136-140° C.; MS: m/e 1273.4 [M+H];High Resolution MS: Calcd for C₆₈H₇₃N₈O₁₃S₂ [M+H]: 1273.4738, Found:1273.4730.

[0803] Part D—3-((1-Methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicAcid

[0804] The product form Part C, above (295 mg, 0.232 mmol) was dissolvedin a mixture of peroxide-free THF (12 mL), water (1.8 mL), and 3 N LiOH(1.2 mL), and stirred at ambient temperatures under a nitrogenatmosphere for 30 min. The THF was removed under vacuum and theresulting mixture was dissolved in CHCl₃ (75 mL) and water (50 mL). Theaqueous layer was adjusted to pH 3 with 0.5 N HCl and the layers werethoroughly mixed. The aqueous layer was extracted with additional CHCl₃(2×25 mL). The combined CHCl₃ extracts were washed with saturated NaCl(50 mL), dried (MgSO₄), and concentrated to give the title compound as apale yellow solid (291 mg, 100%). MS: m/e 1259.3 [M+H]; High ResolutionMS: Calcd for C₆₇H₇₁N₈O₁₃S₂ [M+H]: 1259.4582, Found: 1259.4610.

[0805] PartE—2-(((4-(4-(((3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-yl)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid

[0806] The product from Part D, above (279 mg, 0.222 mmol) was dissolvedin degassed TFA (30 mL) and treated with Et₃SiH (0.424 mL, 2.66 mmol).The solution was heated at 70° C. under a nitrogen atmosphere for 1 hand concentrated to a viscous oil. This oil was dissolved in water (20mL) and washed with ether (2×20 mL). The combined ether washings wereback-extracted with water (10 mL). The combined water extracts werediluted with an equal volume of ACN and treated with Bio-Rad AG-3-X4Aresin, hydroxide form to raise the pH from 4 to 6. The resin was removedby filtration and the filtrate was lyophilized to give the titlecompound as a colorless solid (220 mg). MS: m/e 883.4 [M+H], 442.5[M+2H]; High Resolution MS: Calcd for C₄₀H₅₁N₈O₁₁S₂ [M+H]: 833.3118,Found: 833.3118.

[0807] PartF—2-(((4-(4-(((3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt

[0808] A solution of the product from Part F, above (15 mg, 0.0135mmol), TEA (0.007 mL), and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (9.0 mg, 0.0204 mmol) in anhydrous DMF (2.5 mL) was allowed tostand at ambient temperatures under a nitrogen atmosphere for 22 h. TheDMF was removed under vacuum and the glassy solid was dissolved in 20%ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm)using 0.1% TFA in water for 5 min followed by a 2.52%/min gradient of 0to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The mainproduct peak eluting at 21.2 min was collected and lyophilized to givethe title compound as a colorless powder (3.5 mg, 20%). MS: m/e 1186.7[M+H]; High Resolution MS: Calcd for C₅₃H₆₀N₁₁O₁₅S₃ [M+H]: 1186.3432,Found: 1186.3410.

Example 23-((7-((Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicAcid Bis(trifluoroacetate) Salt

[0809] Part A—Phenylmethyl2-(1,4,7,10-Tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate

[0810] A solution of tert-butyl(1,4,7,10-tetraaza-4,7-bis(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate(0.922 g, 1.79 mmol), TEA (1.8 mL) and benzyl bromoacetate (0.86 mL,5.37 mmol) in anhydrous DMF (24 mL) was stirred at ambient temperaturesunder a nitrogen atmosphere for 24 h. The DMF was removed under vacuumand the resulting oil was dissolved in EtOAc (300 mL). This solution waswashed consecutively with water (2×50 mL) and saturated NaCl (50 mL),dried (MgSO₄), and concentrated to give the title compound as anamorphous solid (1.26 g). MS: m/e 663.5 [M+H].

[0811] PartB—2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid

[0812] The product from Part A, above (165 mg, 0.25 mmol) washydrogenolyzed over 10% Pd on carbon (50 mg) in EtOH (15 mL) at 60 psifor 24 h. The catalyst was removed by filtration through filter aid andwashed with EtOH. The filtrates were concentrated to give the titlecompound as an amorphous solid (134 mg, 94%). MS: m/e 573.5 [M+H].

[0813] Part C—Methyl3-((7-((Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoatePentakis(trifluoroacetate) Salt

[0814] A solution of the product of Example 1, Part C (68 mg, 0.0534mmol) and Et₃SiH (0.051 mL, 0.32 μmol) in degassed TFA (5.0 mL) wasstirred at 70° C. under a nitrogen atmosphere for 1 h and concentratedto dryness. The resulting amber oil was dissolved in anhydrous DMF (2mL) and treated with TEA until basic to pH paper. A solution of theproduct of Part B, above (46 mg, 0.080 mmol) in anhydrous DMF (1.0 mL)was added, followed by HBTU (24 mg, 0.064 mmol), and the solution wasstirred at ambient temperatures under a nitrogen atmosphere for 3 h. TheDMF was removed under vacuum and the residue was dissolved in 50% ACNand purified by preparative HPLC on a Vydac C-18 column (22×250 mm)using a 2.1%/min gradient of 0 to 63% ACN containing 0.1% TFA at a flowrate of 20 mL/min. The main product peak eluting at 23.8 min wascollected and lyophilized to give the title compound as a colorlesspowder (16 mg, 15%). MS: m/e 1451.7 [M+H]; High Resolution MS: Calcd forC₆₉H₁₀₃N₁₂O₁₈S₂ [M+H]: 1451.6954, Found: 1451.698.

[0815] PartD—3-((7-((Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicAcid Bis(trifluoroacetate) Salt

[0816] The product of Part C, above (16 mg, 0.0102 mmol) was dissolvedin a mixture of peroxide-free THF (1 mL), water (0.115 mL), and 3 N LiOH(0.075 mL), and stirred at ambient temperatures under a nitrogenatmosphere for 24 h. The reaction was concentrated to give an oilysolid. This solid was dissolved in 50% ACN and purified by preparativeHPLC on a Vydac C-18 column (22×250 mm) using a 2.52%/min gradient of 0to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The mainproduct peak eluting at 24.0 min was collected and lyophilized to give acolorless powder (6.0 mg). This solid was dissolved in degassed TFA (2.0mL) and Et₃SiH (0.050 mL), stirred at 70° C. under a nitrogen atmospherefor 4.5 h, and concentrated to dryness. The resulting oil was dissolvedin 25% ACN and purified by preparative HPLC on a Vydac C-18 column(22×250 mm) using a 1.5%/min gradient of 0 to 45% ACN containing 0.1%TFA at a flow rate of 20 mL/min. The main product peak eluting at 19.0min was collected and lyophilized to give the title compound as acolorless powder (2.0 mg, 17%). MS: m/e 1269.5 [M+H], 635.5 [M+2H],424.3 [M+3H]; High Resolution MS: Calcd for C₅₆H₇₇N₁₂O₁₈S₂ [M+H]:1269.4920, Found: 1269.4950.

Example 32-(((4-(3-(N-(3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt

[0817] Part A—Ethyl 4-(3,5-Dimethylphenoxy)butanoate

[0818] Sodium metal (17.12 g, 0.744 mol) was added to anhydrous EtOH(350 mL) and stirred until dissolved. 3,5-Dimethylphenol was added andthe solution was stirred 15 min at ambient temperatures. Ethyl4-bromoacetate (58.7 mL, 0.41 mol) was added and the solution wasstirred at ambient temperatures under a nitrogen atmosphere for 28 h.The EtOH was removed under vacuum and the oily solid was partitionedbetween water (1 L) and EtOAc (500 mL). The aqueous layer was extractedwith additional EtOAc (500 mL). The combined EtOAc extracts were washedconsecutively with saturated NaHCO₃ (300 mL) and saturated NaCl (300mL), dried (MgSO₄), and concentrated to give an amber liquid. Thisliquid was vacuum fractional distilled through a 15 cm Vigreux column.The main fraction was collected from 91-117° C./6 mm Hg to gave thetitle compound as a colorless liquid (77.77 g, 89%). ¹H NMR (CDCl₃):6.59 (s, 1H), 6.52 (s, 2H), 4.16 (q, J=7.16 Hz, 2H), 3.98 (t, J=6.14 Hz,2H), 2.49 (t, J=7.34 Hz, 2H), 2.28 (s, 6H), 2.11-2.07 (m, 2H), 1.26 (t,J=7.16 Hz, 3H); Anal. calcd for C₁₄H₂₀O₃: C, 71.16; H, 8.53, Found: C,71.35; H, 8.59.

[0819] Part B—4-(3,5-Dimethylphenoxy)butanoic Acid

[0820] The product of part A, above (75.52 g, 0.320 mol) and KOH pellets(38.5 g, 0.584 mol) were dissolved in absolute EtOH (1.50 L) and heatedat reflux for 3 h. The solution was concentrated to a colorless solid,which was taken up in water (2.0 L) and washed with ether (2×750 mL).The aqueous layer was adjusted to pH 1 with concd HCl (55 mL) and theresulting oily ppt was extracted into EtOAc (2×500 mL). The combinedEtOAc extracts were washed consecutively with water (300 mL) andsaturated NaCl, dried (MgSO₄), and concentrated to give a colorlesssolid (64.13 g). Recrystallization from hexanes (500 mL) gave the titlecompound as a colorless solid (59.51 g, 89%). MP: 66-68.5° C.; ¹H NMR(CDCl₃): 11.70 (bs, 1H), 6.59 (S, 1H), 6.52 (S, 2H), 3.99 (t, J=6.06 Hz,2H), 2.57 (t, J=7.29 Hz, 2H), 2.28 (s, 6H), 2.12-2.08 (m, 2H); Anal.calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74, Found: C, 69.23; H, 7.40.

[0821] Part C—4-(4-(Chlorosulfonyl)-3,5-dimethylphenoxy)butanoic Acid

[0822] A solution of the product of Part B, above (20.8 g, 0.100 mol) inCHCl₃ (100 mL) was cooled to 0° C. and treated with chlorosulfonic acid(36 mL, 0.54 mol) dropwise and with rapid stirring while keeping thetemperature of the reaction at 0° C. The resulting gelatinous mixturewas stirred an additional 10 min and poured onto an ice/water mixture(600 mL). The resulting solid ppt was collected by filtration, washedwith water (3×75 mL), and dried under vacuum to give a colorless solid(12.52 g). MP: 114-115° C. (with decomp); ¹H NMR (CDCl₃): 13.84 (bs,1H), 6.50 (s, 2H), 3.91 (t, J=6.48 Hz, 2H), 2.48 (s, 6H), 2.32 (t,J=7.32 Hz, 2H), 1.89-1.84 (m, 2H); IR (KBr cm⁻¹): 1705 (s), 1370 (s),1175 (s); MS: m/e 305.1 [M−H].

[0823] PartD—4-(4-(((2-((tert-Butoxy)carbonylamino)-1-(methoxycarbonyl)ethyl)amino)sulfonyl)-3,5-dimethylphenoxy)butanoicAcid

[0824] A solution of N-β-Boc-L-α,β,-diaminopropionic acid methyl esterhydrochloride (568 mg, 2.10 mmol) and DIEA (0.73 mL, 4.2 mmol) in DCM (5mL) was cooled to 0° C. and treated with a suspension of the product ofPart C, above (656 mg, 2.10 mmol) in DCM (20 mL) in small portions overa 15 min period. The reaction was stirred at ambient temperatures undera nitrogen atmosphere for 18 h. The reaction was diluted with DCM (100mL) and washed with water (3×75 mL). The organic phase was dried(MgSO₄), and concentrated to give crude product (698 mg), which waspurified by preparative HPLC on a Vydac C-18 column (50×250 mm) using a0.96%/min gradient of 18 to 58.5% ACN containing 0.1% TFA at a flow rateof 80 mL/min. The main product fraction eluting at 23.8 min wascollected adjusted to pH 3, partially concentrated to remove ACN, andextracted with DCM (2×100 mL). The DCM extracts were dried (MgSO₄) andconcentrated to give the title compound as a colorless solid (297 mg,29%). ¹H NMR (CDCl₃): δ 6.61 (s, 2H), 5.66 (d, J=7.2 Hz, 1H), 4.90 (s,1H), 4.03 (bs, 2H), 3.86 (bs, 1H), 3.59 (s, 3H), 3.49 (bs, 2H), 2.62 (s,6H), 2.58-2.51 (m, 2H), 2.18-2.07 (m, 2H), 1.41 (s, 9H); MS: m/e 489.4[M+H]; High Resolution MS: Calcd for C₂₁H₃₃N₂O₉S [M+Na]: 511.1726,Found: 511.1747; Anal. calcd for C₂₁H₃₂N₂O₉S: C, 51.62; H, 6.61; N,5.74, Found: C, 51.47; H, 6.27; N, 5.48.

[0825] Part E—Methyl3-((tert-Butoxy)carbonylamino)-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate

[0826] A solution of the product from Part D, above (233 mg, 0.477mmol), the product of Example 1, Part A (190 mg, 0.536 mmol), TEA (0.2mL, 1.43 mmol), and HBTU (226 mg, 0.701 mmol) in anhydrous DMF (8 mL)was stirred at ambient temperatures under a nitrogen atmosphere for 1 h.The DMF was removed under vacuum and the oily residue was taken up inEtOAc (50 mL) and washed consecutively with 0.1 N HCl (35 mL), water (35mL), and saturated NaCl (35 mL), dried (MgSO₄), and concentrated to givecrude product as a yellow viscous oil. Flash chromatography on a 3×18 cmsilica gel column (EtOAc/MeOH, 95/5) gave the title compound as acolorless viscous oil (393 mg, 100%). ¹H NMR (CDCl₃): δ 7.34-7.28 (m,5H), 6.60 (s, 2H), 6.26 (bs, 1H), 5.67 (bs, 1H), 5.29 (bs, 1H), 5.08 (s,2H), 4.88 (bs, 1H), 3.99 (t, J=6.1 Hz, 2H), 3.88-3.84 (m, 1H), 3.62-3.40(m, 17H), 3.37-3.26 (m, 4H), 2.62 (s, 6H), 2.32 (t, J=7.2 Hz, 2H), 2.08(t, J=6.3 Hz, 2H), 1.79-1.70 (m, 4H), 1.41 (s, 9H); MS: m/e 825.5 [M+H];High Resolution MS: Calcd for C₃₉H₆₁N₄O₁₃S [M+H]: 825.3955, Found:825.3940.

[0827] Part F—Methyl3-Amino-2-(((2,6-dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)propanoate

[0828] The product of Part E, above (750 mg, 0.91 mmol) was dissolved in4 M HCl/dioxane (25 mL) and stirred at ambient temperatures for 1 h. Thesolution was diluted with ether (500 mL) and the resulting gummy ppt wastriturated with fresh ether (2×250 mL). The gummy solid was dissolved inwater (100 mL) and adjusted to pH 9 with NaHCO₃, causing an oily ppt toform. This ppt was extracted into DCM (2×75 mL). The DCM extracts weredried (MgSO₄) and concentrated to give the title compound as a colorlessoil (386 mg, 56%). MS: m/e 725.5 [M+H].

[0829] Part G—Methyl2-(((2,6-Dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)-3-((1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)propanoate

[0830] A solution of1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)hydroquinoline-3-carboxylicacid (274 mg, 0.51 mmol), TEA (0.22 mL, 1.52 mmol), and HBTU (192 mg,0.51 mmol) in anhydrous DMF (3 mL) was stirred at ambient temperaturesfor 5 min. A solution of the product of Part F, above (367 mg, (0.51mmol) in anhydrous DMF (7 mL) was added and the resulting solution wasstirred at ambient temperatures under a nitrogen atmosphere for 2 h. TheDMF was removed under vacuum and the resulting oily solid was dissolvedin EtOAc (150 mL). The EtOAc solution was washed consecutively withwater (50 mL), saturated NaHCO₃ (25 mL), and saturated NaCl (25 mL),dried (MgSO₄), and concentrated to give a yellow solid. Purification byflash chromatography on a silica gel column using a EtOAc/MeOH stepgradient (95/5, 92.5/7.5) gave the title compound as a pale yellow solid(254 mg, 43%). MS: m/e 1247.7 [M+H], 624.6 [M+2H].

[0831] PartH—2-(((2,6-Dimethyl-4-(3-(N-(3-(2-(2-(3-((phenylmethoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)phenyl)sulfonyl)amino)-3-((1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)propanoicAcid

[0832] The product of Part G, above (60.0 mg, 0.048 mmol) was dissolvedin a mixture of peroxide-free THF (2.5 mL), water (0.37 mL), and 3 NLiOH (0.244 mL), and stirred at ambient temperatures under a nitrogenatmosphere for 30 min. The THF was removed under vacuum and theresulting mixture was dissolved in CHCl₃ (25 mL) and water (20 mL). Theaqueous layer was adjusted to pH 3 with 0.1 N HCl and the layers werethoroughly mixed. The aqueous layer was extracted with additional CHCl₃(2×20 mL). The combined CHCl₃ extracts were washed with saturated NaCl(30 mL), dried (MgSO₄), and concentrated to give the title compound as apale yellow solid (44.0 mg, 74%). MS: m/e 1233.7 [M+H]; High ResolutionMS: Calcd for C₆₇H₇₇N₈O₁₃S [M+H]: 1233.5330, Found: 1233.5330.

[0833] PartI—2-(((4-(3-(N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid

[0834] The product of Part H, above (42.1 mg, 0.0341 mmol) and Et₃SiH(0.033 mL, 0.205 mmol) were dissolved in degassed TFA (3.5 mL), heatedat 70° C. under a nitrogen atmosphere for 1 h, and concentrated to givea viscous amber oil. This oil was dissolved in water (20 mL) and washedwith ether (2×20 mL). The combined ether washings were back-extractedwith water (10 mL). The combined water extracts were diluted with anequal volume of ACN and treated with Bio-Rad AG-3-X4A resin, hydroxideform to raise the pH from 4 to 6. The resin was removed by filtrationand the filtrate was lyophilized to give the title compound as acolorless solid (34 mg). MS: m/e 857.5 [M+H], 429.4 [M+2H].

[0835] Part J—2-(((4-(3-(N-(3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl) amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino) propanoic Acid Trifluoroacetate Salt

[0836] A solution of the product from Part I, above (30 mg, 0.035 mmol),DIEA (0.018 mL, 0.105 μmol) and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (18.5 mg, 0.042 mmol) in anhydrous DMF (1.5 mL) was allowed tostand at ambient temperatures under a nitrogen atmosphere for 20 h. TheDMF was removed under vacuum and the amber oil was dissolved in 50% ACNand purified by preparative HPLC on a Zorbax C-18 RX column (21.2×250mm) using a 1.5%/min gradient of 0 to 45% ACN containing 0.1% TFA at aflow rate of 20 mL/min. The main product peak eluting at 21.0 min wascollected and lyophilized to give the title compound as a colorlesspowder (8.9 mg, 20%). MS: m/e 1160.6 [M+H], 581.0 [M+2H].

Example 43-((1-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0837] Part A—Ethyl1-(3-((tert-Butoxy)carbonylamino)propyl)-7-bromo-4-oxohydroquinoline-3-carboxylate

[0838] A mixture of ethyl 7-bromo-4-oxohydroquinoline-3-carboxylate(6.28 g, 0.0212 mol), (tert-butoxy)-N-(3-bromopropyl)formamide (30.3 g,0.127 mol), and anhydrous K₂CO₃ (12.5 g, 0.904 mol) in anhydrous DMF(200 mL) was stirred at 60° C. under a nitrogen atmosphere for 4 h, andthen at ambient temperatures for 72 h. The DMF was removed under vacuumand the resulting oily solid was dissolved in EtOAc (500 mL). The EtOAcsolution was washed consecutively with water (500 mL), saturated NaHCO₃(500 mL), and saturated NaCl (500 mL), dried (MgSO₄), and concentratedto give a red oil. This oil was taken up in EtOAc (250 mL) and cooled,causing a solid ppt to form. This ppt was collected by filtration,washed with cold EtOAc, and dried to give the title compound as acolorless solid (6.25 g, 65%). MP: 140-142° C.; ¹H NMR (CDCl₃): 8.49 (s,1H), 8.39 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 4.72(bs, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.20 (t, J=7.6 Hz, 2H), 3.28-3.24 (m,2H), 2.10-2.06 (m, 2H), 1.46 (s, 9H), 1.40 (t, J=7.1 Hz, 3H); MS: m/e455.2. [M+H]; High Resolution MS: Calcd for C₂₀H₂₆BrN₂O₅ [M+H]:453.1025, Found: 453.1028.

[0839] Part B—Ethyl1-(3-((tert-Butoxy)carbonylamino)propyl)-4-oxo-7-vinylhydroquinoline-3-carboxylate

[0840] The product from Part A, above (2.98 g, 6.60 mmol) was dissolvedin toluene (50 mL) at a temperature of 100° C. and treated withtetrakis(triphenylphosphine)palladium(0)(152 mg, 0.132 mmol). After 5min the mixture was treated with tributyl(vinyl)tin (1.93 mL, 6.60 mmol)and stirred 4.5 h at 100° C. under a nitrogen atmosphere, and 18 h atambient temperatures. Additional tributyl(vinyl)tin (0.386 mL) andtetrakis(triphenylphosphine)palladium(0) (152 mg) were added and themixture was heated at 100° C. for an additional 17 h. The toluene wasremoved under vacuum and the solid residue was triturated with ether togive the title compound as a pale green solid (1.67 g, 63%). MP:133-135° C.; ¹H NMR (CDCl₃): 8.52 (d, J=8.4 Hz, 1H), 8.51 (s, 1H), 7.55(d, J=8.4 Hz, 1H), 7.38 (s, 1H), 6.88-6.82 (m, 1H), 5.97 (d, J=17.4 Hz,1H), 5.51 (d, J=10.8 Hz, 1H), 4.75 (bs, 1H), 4.42 (q, J=7.2 Hz, 2H),4.27 (t, J=7.8 Hz, 2H), 3.6-3.25 (m, 2H), 2.16-2.11 (m, 2H), 1.49 (s,9H), 1.45 (t, J=7.2 Hz, 3H); MS: m/e 401.3 [M+H]; High Resolution MS:Calcd for C₂₂H₂₉N₂O₅ [M+H]: 401.2076, Found: 401.2075.

[0841] Part C—Ethyl1-(3-((tert-Butoxy)carbonylamino)propyl)-7-formyl-4-oxohydroquinoline-3-carboxylate

[0842] A solution of the product of Part B, above (1.50 g, 3.75 mmol) indioxane (119 mL) and water (39 mL) was treated with a solution of osmiumtetroxide (19.6 mg, 0.077 mmol) in dioxane (0.600 mL) and stirred atambient temperatures under a nitrogen atmosphere for 5 min. Sodiumperiodate (2.40 g, 11.2 mmol) was added and the stirred at ambienttemperatures for 2 h. The dioxane was removed under vacuum and theresidue was taken up in DCM (500 mL). The DCM solution was washedconsecutively with water (500 mL) and saturated NaCl (500 mL), dried(MgSO₄), and concentrated to give the title compound as an orange oilysolid (1.52 g, 100%). ¹H NMR (CDCl₃): 10.17 (s, 1H), 8.68 (d, J=8.2 Hz,1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 4.82 (bs, 1H),4.41-4.35 (m, 4H), 3.28 (s, 2H), 2.15-2.07 (m, 2H), 1.45 (s, 9H), 1.41(t, J=7.1 Hz, 3H); MS: m/e 403.3 [M+H]; High Resolution MS: Calcd forC₂₁H₂₇N₂O₆ [M+H]: 403.1870, Found: 403.1875.

[0843] Part D—Ethyl1-(3-((tert-Butoxy)carbonylamino)propyl)-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)hydroquinoline-3-carboxylate

[0844] A solution of the product of Part C, above (544 mg, 1.35 mmol)and 1-(triphenylmethyl)imidazole-2-ylamine (456 mg, 1.35 mmol) intoluene (60 mL) was heated at reflux under a nitrogen atmosphere withremoval of water for 5 h. The solution was cooled, treated withNa(OAc)₃BH (1.14 g, 5.38 mmol) and stirred at ambient temperatures for18 h. The mixture was diluted with EtOAc (400 mL), washed consecutivelywith water (500 mL) and saturated NaCl (500 mL), dried (MgSO₄), andconcentrated to give an orange solid. This solid was dissolved in 50%ACN and purified by preparative HPLC on a Vydac C-18 column (50×250 mm)using a 0.60%/min gradient of 18 to 52% ACN containing 0.1% TFA at aflow rate of 49 mL/min. The main product peak eluting at 30.8 min wascollected and lyophilized to give the title compound as a pale yellowsolid (407 mg, 60%). MS: m/e 712.4 [M+H]; High Resolution MS: Calcd forC₄₃H₄₆N₅O₅ [M+H]: 712.3499, Found: 712.3485.

[0845] PartE—1-(3-((tert-Butoxy)carbonylamino)propyl)-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)hydroquinoline-3-carboxylicAcid

[0846] A mixture of the product of Part D, above (997 mg, 1.40 mmol),water (7.3 mL), 3 N LiOH (3.5 mL), and THF (50 mL) was stirred atambient temperatures under a nitrogen atmosphere for 3 h. The THF wasremoved under vacuum and the resulting mixture was dissolved in CHCl₃(500 mL) and water (100 mL). The aqueous layer was adjusted to pH 3 with1.0 N HCl and the layers were thoroughly mixed. The organic layer waswashed consecutively with water (500 mL) and saturated NaCl (500 mL),dried (MgSO₄), and concentrated to give the title compound as a paleyellow solid (998 mg). MP: 153-160 ° C.; ¹H NMR (CDCl₃): δ 14.83 (s,1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.24 (d, J=6 Hz, 1H), 7.49-7.35 (m,9H), 7.12-7.10 (m, 6H), 6.82 (s, 1H), 6.52 (s, 1H), 6.24 (d, J=6 Hz,1H), 5.75 (bs, 1H), 4.87-4.83 (m, 2H), 4.77 (bs, 1H), 4.51 (t, J=9 Hz,2H), 3.38 (s, 2H), 2.23 (s, 2H), 1.42 (s, 9H); MS: m/e 684.3 [M+H]; HighResolution MS: Calcd for C₄₁H₄₂N₅O₅ [M+H]: 684.3186, Found: 684.3181.

[0847] Part F—Methyl3-((1-(3-((tert-Butoxy)carbonylamino)propyl)-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoate

[0848] A solution of the product of Part E, above (300 mg, 0.437 mmol),TEA (0.243 mL, 1.75 mmol), and HBTU (230 mg, 0.606 mmol) in anhydrousDMF (4 mL) was stirred at ambient temperatures for 5 min. A solution ofmethyl 3-amino-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoatehydrochloride (184 mg, 0.637 mmol) in anhydrous DMF (3 mL) was added andthe solution was stirred at ambient temperatures under a nitrogenatmosphere for 2 h. The solution was diluted with EtOAc (200 mL) andwashed consecutively with water (2×50 mL), saturated NaHCO₃ (50 mL), andsaturated NaCl (50 mL), dried (MgSO₄), and concentrated to give aviscous amber oil. Purification by flash chromatography on a 2.5×24 cmsilica gel column using a EtOAc/MeOH step gradient (98/2, 95/5, 75/25)gave the title compound as a pale yellow oil (330 mg, 78%). MS: m/e966.6 [M+H]; High Resolution MS: Calcd for C₅₄H₆₀N₇O₈S [M+H]: 966.4224,Found: 966.4224.

[0849] PartG—3-((1-(3-((tert-Butoxy)carbonylamino)propyl)-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid

[0850] A solution of the product of Part F, above (51 mg, 0.052 mmol),water (0.27 mL), and 3 N LiOH (0.13 mL) in MeOH (2 mL) was allowed tostand at ambient temperatures for 3.5 h and concentrated under vacuum.The resulting solid was dissolved in water (10 mL) and adjusted to pH 3with 1.0 N HCl. The aqueous mixture was extracted with DCM (2×30 mL).The combined DCM extracts were washed with saturated NaCl (30 mL), dried(MgSO₄), and concentrated to give the title compound as a colorlesssolid (72 mg). MS: m/e 952.5 [M+H]; High Resolution MS: Calcd forC₅₃H₅₈N₇O₈S [M+H]: 952.4067, Found: 952.4056.

[0851] PartH—3-((1-(3-Aminopropyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Bis(trifluoroacetate) Salt

[0852] The product of Part I, above (0.052 mmol) and Et₃SiH (0.042 mL,0.26 mmol) were dissolved in degassed TFA (2 mL), heated at 70° C. for2.5 h, and concentrated to give an amber oil. This oil was dissolved inwater (25 mL) and washed with ether (2×15 mL). The combined etherwashings were back-extracted with water (15 mL). The combined waterextracts were lyophilized to give the title compound as a colorlesspowder (34 mg, 78%). MS: m/e 610.4 [M+H]; High Resolution MS: Calcd forC₂₉H₃₆N₇O₆S [M+H]: 610.2448, Found: 610.2462.

[0853] PartI—3-((1-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0854] A solution of the product of Part H, above (13.7 mg, 0.0163mmol), TEA (0.015 mL, 0.108 mmol), and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (8.2 mg, 0.0186 mmol) in anhydrous DMF (2.0 mL) was allowed tostand at ambient temperatures under a nitrogen atmosphere for 24 h. TheDMF was removed under reduced pressure and the amber oil was dissolvedin 50% ACN and purified by preparative HPLC on a Vydac C-18 column(22×250 mm) using 0.1% TFA in water for 5 min followed by a 2.52%/mingradient of 0 to 63% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 21.4 min was collected andlyophilized to give the title compound as a colorless powder (12.5 mg,75%). MS: m/e 913.3 [M+H]; High Resolution MS: Calcd for C₄₂H₄₅N₁₀O₁₀S₂[M+H]: 913.2761, Found: 913.2751.

Example 53-((1-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0855] Part A—Methyl3-((1-(3-Aminopropyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoateBis(trifluoroacetate) Salt

[0856] A solution of the product of Example 4, Part F (120 mg, 0.124mmol) and Et₃SiH (0.99 mL, 6.20 mmol) in TFA (10 mL) was heated at 70°C. for 1 h, and concentrated to give an amber oil. This oil wasdissolved in water (50 mL) and washed with ether (2×30 mL). The combinedether washings were back-extracted with water (20 mL). The combinedwater extracts were lyophilized to give the title compound as acolorless powder (105 mg, 100%). MS: m/e 624.4 [M+H]; High ResolutionMS: Calcd for C₃₀H₃₈N₇O₆S [M+H]: 624.2604, Found: 624.2608.

[0857] PartB—3-((1-(3-Aminopropyl)-7-(((1-hydroxyimidazol-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0858] A mixture of the product of Part A, above (105 mg, 0.126 mmol),water (3.0 mL), and 3 N LiOH (1.82 mL) in peroxide-containing THF (4 mL)was allowed to stand at ambient temperatures for 1 h and concentratedunder vacuum. The resulting solid was dissolved in water (10 mL) andadjusted to pH 5 with 1.0 N HCl. Insoluble impurities were removed byfiltration and the filtrate was lyophilized to give a colorless solid.This solid was dissolved in water and purified by preparative HPLC on aVydac C-18 column (22×250 mm) using 0.1% TFA in water for 5 min followedby a 2.52%/min gradient of 0 to 63% ACN containing 0.1% TFA at a flowrate of 20 mL/min. The main product peak eluting at 19.5 min wascollected and lyophilized to give the title compound as a colorlesspowder (10.0 mg, 11%). MS: m/e 314.0 [M+2H]

[0859] PartC—3-((1-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0860] A solution of the product of Part B, above (10.0 mg, 0.0135mmol), TEA (0.018 mL, 0.129 mmol), and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (7.2 mg, 0.0163 mmol) in anhydrous DMF (4 mL) was allowed to standat ambient temperatures under a nitrogen atmosphere for 20 h. The DMFwas removed under vacuum and the amber oil was dissolved in 30% ACN andpurified by preparative HPLC on a Vydac C-18 column (22×250 mm) using0.1% TFA in water for 5 min followed by a 2.52%/min gradient of 0 to 63%ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main productpeak eluting at 21.5 min was collected and lyophilized to give the titlecompound as a colorless powder (3.5 mg, 25%). MS: m/e 929.4 [M+H]; HighResolution MS: Calcd for C₄₂H₄₅N₁₀O₁₁S₂ [M+H]: 929.2710, Found:929.2698.

Example 63-((1-(3-(3-(N-(3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0861] PartA—3-(N-(3-(2-(2-(3-((tert-Butoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoicAcid

[0862] A solution ofN-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)(tert-butoxy)formamide(as described by D. S. Wilbur et al. in Bioconjugate Chem. 1998, 9,322-330)(2.00 g, 6.24 mmol), TEA (1.0 mL, 7.49 mmol), and succinicanhydride (624 mg, 6.24 mmol) in anhydrous DMF (5 mL) was stirred atambient temperatures under a nitrogen atmosphere for 4 h. The DMF wasremoved under reduced pressure to give the title compound as a paleyellow oil (2.80 g). MS: m/e 839.5 [2M−H], 419.4 [M−H].

[0863] Part B—Methyl3-((1-(3-(3-(N-(3-(2-(2-(3-((tertButoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoate

[0864] The product of Example 4, Part F (46.1 mg, 0.477 mmol) wasdissolved in 50% TFA/DCM (2.0 mL) for 15 min at ambient temperatures andconcentrated to give a yellow oil. This oil was dissolved in anhydrousDMF (1.0 mL) and made basic to pH paper with TEA. In a separate flask,the product of Part A, above (26.1 mg, 0.062 mmol), TEA (0.014 mL, 0.099mmol), and HBTU (27.7 mg, 0.074 mmol) were dissolved in anhydrous DMF(1.0 mL). The resulting solution was allowed to react for 5 min andcombined with the DMF solution from the TFA deprotection reaction. Thecombined solutions were allowed to stand at ambient temperatures under anitrogen atmosphere for 20 min and concentrated under vacuum. Theresulting oil was dissolved in 50% ACN and purified by preparative HPLCon a Vydac C-18 column (22×250 mm) using a 1.8%/min gradient of 18 to72% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The mainproduct peak eluting at 26.8 min was collected and lyophilized to givethe title compound as a colorless powder (44.5 mg, 68%). MS: m/e 1268.6[M+H]; High Resolution MS: Calcd for C₆₈H₈₆N₉O₁₃S [M+H]: 1268.6065,Found: 1268.6070.

[0865] PartC—3-((1-(3-(3-(N-(3-(2-(2-(3-((tertButoxy)carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid

[0866] A solution of the product of Part B, above (31.1 mg, 0.0227mmol), 3 n LiOH (0.091 mL), and water (0.117 mL) in MeOH (1.30 mL) wasstirred at ambient temperatures for 8.5 h. The MeOH was removed undervacuum and the aqueous mixture was diluted with water (30 mL) andadjusted to pH 4 with 1.0 N HCl. The resulting aqueous mixture wasextracted with DCM (2×50 mL). The combined DCM extracts were washed withsaturated NaCl (50 mL), dried (MgSO₄), and concentrated to give thetitle compound as a colorless solid (24.6 mg, 86%).

[0867] PartD—3-((1-(3-(3-(N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Bis(trifluoroacetate) Salt

[0868] A solution of the product of Part C, above (24.6 mg, 0.0194 mmol)and Et₃SiH (0.016 mL, 0.097 mmol) in TFA (2.0 mL) was heated at 70° C.under a nitrogen atmosphere for 3 h, and concentrated to give a yellowsolid. This solid was dissolved in water (50 mL) and washed with ether(2×25 mL). The aqueous layer was lyophilized to give the title compoundas a pale yellow solid (20.7 mg, 93%). MS: m/e 912.5 [M+H].

[0869] PartE—3-((1-(3-(3-(N-(3-(2-(2-(3-((6-((1-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Trifluoroacetate Salt

[0870] A solution of the product of Part D, above (15.5 mg, 0.0136mmol), TEA (0.010 mL, 0.0746 mmol), and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (8.0 mg, 0.0182 mmol) in anhydrous DMF (2.0 mL) was allowed tostand at ambient temperatures under a nitrogen atmosphere for 24 h. TheDMF was removed under vacuum and the resulting yellow oil was dissolvedin 50% ACN and purified by preparative HPLC on a Vydac C-18 column(22×250 mm) using 0.1% TFA in water for 5 min followed by a 2.52%/mingradient of 0 to 63% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 21.7 min was collected andlyophilized to give the title compound as a colorless powder (7.2 mg,40%). MS: m/e 1215.5 [M+H]; High Resolution MS: Calcd for C₅₆H₇₁N₁₂O₁₅S₂[M+H]: 1215.4603, Found: 1215.4580.

Example 72-(2-Aza-2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonicAcid Bis(trifluoroacetate) Salt

[0871] Part A—N,N′-Bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carbomethoxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)hydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl-2-((tert-butoxy)carbonylamino)pentane-1,5-diamide

[0872] A solution of the product of Example 6, Part B (50.5 mg, 0.0398mmol) in 50/50 TFA/DCM (2 mL) was allowed to react for 20 min at ambienttemperatures and concentrated to a viscous oil. This oil was taken up inanhydrous DMF and made basic to pH paper with TEA. This solution wastreated with Boc-L-Glu-OH (4.5 mg, 0.0181 mmol) and HBTU (16.6 mg,0.0438 mmol), and allowed to stand at ambient temperatures for 2 h. TheDMF was removed under vacuum and the resulting oil was dissolved in 60%ACN and purified by preparative HPLC on a Vydac C-18 column (22×250 mm)using a 1.8%/min gradient of 18 to 72% ACN containing 0.1% TFA at a flowrate of 20 mL/min. The main product peak eluting at 21.5 min wascollected and lyophilized to give the title compound as a colorlesspowder (38.8 mg, 84%). MS: m/e 2306.5 [M+H-Tr], 2064.4 [M+H-2Tr], 1275.0[M+2H]; High Resolution MS: Calcd for C₁₁₇H₁₅₄N₁₉OS₂ [M+H-Tr]:2305.0753, Found: 2305.0770.

[0873] PartB—2-Amino-N,N′-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)pentane-1,5-diamide Tris(trifluoroacetate) Salt

[0874] A solution of the product from Part A, above (38.8 mg, 0.0152mmol), 3 N LiOH (0.075 mL), and water (0.156 mL) in MeOH (2.0 mL) wasstirred at ambient temperatures for 18 h. The MeOH was removed undervacuum and the aqueous mixture was diluted with water (50 mL) andadjusted to pH 3 using 0.5 N HCl. The mixture was extracted with DCM(2×50 mL). The combined DCM extracts were washed with saturated NaCl (50mL), dried (MgSO₄), and concentrated to give a colorless solid. Thissolid was dissolved in TFA (3.0 mL) along with Et₃SiH (0.031 ML, 0.178mol), heated at 70° C. under a nitrogen atmosphere for 11 h, andconcentrated to give a yellow oil. This oil was dissolved in water (25mL) and washed with ether (2×25 mL). The aqueous solution waslyophilized to give a pale yellow solid. This solid was dissolved inwater and purified by preparative HPLC on a Vydac C-18 column (22×250mm) using 0.1% TFA in water for 5 min followed by a 2.52%/min gradientof 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. Themain product peak eluting at 22.4 min was collected and lyophilized togive the title compound as a colorless powder (5.1 mg, 18%). MS: m/e968.2 [M+2H], 646.0 [M+3H].

[0875] PartC—2-(2-Aza-2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl) 4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonicAcid Bis(trifluoroacetate) Salt

[0876] A solution of the product of Part B, above (5.1 mg, 0.00224mmol), TEA (0.002 mL, 0.0115 mmol), and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (1.2 mg, 0.00272 mmol) in anhydrous DMF (2.0 mL) was allowed tostand at ambient temperatures under nitrogen for 72 h. The DMF wasremoved under vacuum and the resulting oil was dissolved in 50% ACN andpurified by preparative HPLC on a Vydac C-18 column (22×250 mm) using0.1% TFA in water for 5 min followed by a 2.52%/min gradient of 0 to 63%ACN containing 0.1% TFA at a flow rate of 20 mL/min. The main productpeak eluting at 23.5 min was collected and lyophilized to give the titlecompound as a colorless powder (0.5 mg, 9.0%). MS: m/e 1120.0 [M+2H];High Resolution MS: Calcd for C₁₀₄H₁₃₇N₂₂O₂₈S₃ [M+]: 2237.9055, Found:2237.9120.

Example 8 DOTA Conjugate of 3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp-L-Asp)3-aminopropoxy) ethoxy) ethoxy) propyl) carbamoyl)propanoylamino)propyl-7-((imidazole-2-ylamino) methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino) propanoic Acid Bis(trifluoroacetate Salt

[0877] Part A—Carbobenzyloxy-L-Asp(O-t-Bu)-L-Asp(O-t-Bu)-OMe

[0878] A solution of Cbz-Asp(O-t-Bu)-OH (1.54 g, 4.76 mmol),H-Asp(O-t-Bu)-Ome.HCl (1.14 g, 4.76 mmol), DIEA (1.85 mL, 10.5 mmol),and HBTU (1.99 g, 5.24 mmol) in DMF (20 mL) was stirred at ambienttemperatures for 18 h. Water (100 mL) and EtOAc (50 mL) were added andthe layers were separated. The water layer was extracted with EtOAc(2×50 mL). The combined EtOAc extracts were washed consecutively withwater (50 mL), 10% KHSO₄ (2×50 mL), and 10% NaHCO₃ (50 mL). The organicphase was dried (MgSO₄), and concentrated to give an oily solid. Thismaterial was triturated with ether to give the title compound as acolorless solid (2.14 g, 89%). MS: m/e 1017.6 [2M+H], 509.4 [M+H].

[0879] Part B—Carbobenzyloxy-L-Asp (O-t-Bu)-L-Asp(O-t-Bu)-OH

[0880] A mixture of the product of Part A, above (200 mg, 0.393 mmol),LiOH (38 mg, 0.865 mmol), water (40 mL), and THF (200 mL) was stirred atambient temperatures for 28 h, and concentrated to remove THF. Theaqueous mixture was diluted with additional water (20 mL) and washedwith EtOAc (20 mL). The aqueous phase was adjusted to pH 4 with 1.0 NHCl and extracted with EtOAc (20 mL). The EtOAc extract was washed withsaturated NaCl (15 mL), dried (MgSO₄), and concentrated to give acolorless solid. This solid was dissolved in 60% ACN and purified bypreparative HPLC on a Vydac C-18 column (22×250 mm) using a 2.4%/mingradient of 18 to 90% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 19.0 min was collected andlyophilized to give the title compound as a colorless powder (95 mg,49%).

[0881] Part C—Methyl3-((1-(3-(3-(N-(3-(2-(2-(N-(benzyloxycarbonyl-L-Asp(O-t-Bu)-L-Asp(O-t-Bu))3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoate

[0882] The product of Example 6, Part B (44.0 mg, 0.0894 mmol) in TFA(1.5 mL) was allowed to stand at ambient temperatures for 45 min andconcentrated to a yellow oil. This oil was dissolved in anhydrous DMF(2.0 mL) and made basic to pH paper with TEA. In a separate flask, theproduct of Part B, above (69.3 mg, 0.0547 mmol) was dissolved inanhydrous DMF (2.0 mL) and pre-activated by treatment with TEA (0.015mL, 0.104 mmol) and HBTU (32.6 mg, 0.0859 mmol). After 10 min thissolution was added to the DMF solution from the TFA deprotectionreaction, and the combined solutions were stirred at ambienttemperatures for 30 min. The DMF was removed under vacuum and theresulting oil was dissolved in 60% ACN and purified by preparative HPLCon a Vydac C-18 column (22×250 mm) using a 1.54%/min gradient of 18 to72% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The mainproduct peak eluting at 29.9 min was adjusted to pH 8 with saturatedNaHCO₃ and concentrated to remove the ACN. The remaining aqueous mixturewas extracted with EtOAc (2×40 mL). The combined EtOAc extracts werewashed with saturated NaCl (40 mL), dried (MgSO₄), and concentrated togive the title compound as a colorless solid (56.4 mg, 63%). MS: m/e1644.8 [M+H]; High Resolution MS: Calcd for C₈₇H₁₁₀N₁₁O₁₉S [M+H]:1644.7700, Found: 1644.771.

[0883] Part D—Methyl3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp(O-t-Bu)-L-Asp(O-t-Bu))3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoate

[0884] The product of Part E, above (55.0 mg, 0.0335 mmol) washydrogenolyzed over 10% Pd/C (25 mg) in MeOH (15 mL) at 40 psi for 3.5h. The catalyst was removed by filtration through filter aid and thefiltrate was concentrated to give the title compound as a pale yellowoil (41.8 mg, 83%). MS: m/e 1510.8 [M+H].

[0885] Part E—DOTA-tri-t-butyl Ester Conjugate of Methyl3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp(O-t-Bu)-L-Asp(O-t-Bu))3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-4-oxo-7-(((1-(triphenylmethyl)imidazole-2-yl)amino)methyl)(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoate

[0886] A solution of the product of Part D, above (41.8 mg, 0.0277mmol), the product of Example 2, Part B, 39.9 mg, 0.0436 mmol), TEA(0.023 mL, 0.166 mmol), and HBTU (15.6 mg, 0.0411 mmol) in anhydrous DMF(3.0 mL) was allowed to stand at ambient temperatures under a nitrogenatmosphere for 20 h. The DMF was removed under vacuum and the resultingoil was dissolved in 60% ACN and purified by preparative HPLC on a VydacC-18 column (22×250 mm) using a 2.4%/min gradient of 18 to 90% ACNcontaining 0.1% TFA at a flow rate of 20 mL/min. The main product peakeluting at 21.2 min was collected and lyophilized to give the titlecompound as a colorless powder (24.8 mg, 43%). MS: m/e 2066.3 [M+H],1033.6 [M+2H]; High Resolution MS: Calcd for C₁₀₇H₁₅₄N₁₅O₂₄S [M+H]:2065.1011, Found: 2065.1030.

[0887] Part F—DOTA Conjugate of3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp-L-Asp)3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid Bis(trifluoroacetate Salt

[0888] A mixture of the product of Part G, above (18.8 mg. 0.0091 mmol),water (0.150 mL), 3 N LiOH (0.015 mL), and peroxide-free THF (1.5 mL)was stirred at ambient temperatures for 3 h. The THF was removed undervacuum and the aqueous mixture was diluted with water (40 mL) andadjusted to pH 7 with 0.1 N HCl. The mixture was extracted with DCM(2×30 mL) and the combined extracts were concentrated to give a yellowoil. This oil was dissolved in TFA (1.0 mL) along with Et₃SiH (0.030 mL,0.184 mmol) and heated at 40° C. under a nitrogen atmosphere for 48 h.The solution was concentrated and the resulting oil was dissolved inwater and purified by preparative HPLC on a Vydac C-18 column (22×250mm) using 0.1% TFA in water for 5 min followed by a 2.52%/min gradientof 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 mL/min. Themain product peak eluting at 19.9 min was collected and lyophilized togive the title compound as a colorless powder (1.5 mg, 9.4%). MS: m/e1528.9 [M+2H], 765.1 [M+2H], 510.7 [M+3H].

Example 9DOTA/2-Amino-N,N′-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)pentane-1,5-diamideTris(trifluoroacetate) Salt Conjugate

[0889] Part A—DOTA-tri-t-butylEster/2-Amino-N,N′-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)pentane-1,5-diamideHexakis(trifluoroacetate) Salt Conjugate

[0890] A solution of the product of Example 2, Part B, HBTU, and DIEA inanhydrous DMF is stirred at ambient temperatures under nitrogen for 15min and treated with the product of Example 7, Part B. The resultingsolution is stirred an additional 18 h and the DMF is removed undervacuum. The resulting residue is purified by preparative HPLC on a C₁₈column using a water:ACN:0.1% TFA gradient. The product fraction islyophilized to give the title compound.

[0891] PartB—DOTA/2-Amino-N,N′-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)pentane-1,5-diamideTris(trifluoroacetate) Salt Conjugate

[0892] The product of Part B, above, is dissolved in degassed TFA,treated with triethylsilane, and heated at 50° C. under nitrogen for 1h. The solution is concentrated under vacuum and the resulting residueis purified by preparative HPLC on a C₁₈ column using a water:ACN:0.1%TFA gradient. The product fraction is lyophilized to give the titlecompound.

Example 10DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt Conjugate

[0893] PartA—2-(((4-(3-(N-(3-(2-(2-(3-(2-((tert-Butoxy)carbonylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid

[0894] The product of Example 3, Part I is dissolved in anhydrous DMFand treated with the N-hydroxysuccinimide ester of Boc-cysteic acid (asdescribed in Liebigs Ann. Chem. 1979, 776-783) and DIEA. The solution isstirred at ambient temperatures under nitrogen for 18 h, and the DMF isremoved under vacuum. The resulting residue is purified by preparativeHPLC on a C₁₈ column using a water:ACN:0.1% TFA gradient. The productfraction is lyophilized to give the title compound.

[0895] Part B—DOTA-tri-t-butylEster/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Tetrakis(trifluoroacetate) Salt Conjugate

[0896] The product of Part A, above, is dissolved in degassed TFA andstirred at ambient temperatures for 15 min. The solution is concentratedunder vacuum, and the resulting residue is dissolved in 50% ACN andlyophilized to remove the last traces of TFA.

[0897] In a separate flask, a solution of the product of Example 2, PartB and DIEA in anhydrous DMF are treated with HBTU and allowed to react15 min at ambient temperatures under nitrogen. The deprotected productfrom above is added to this solution and stirring is continued atambient temperatures under nitrogen for 18 h. The DMF is removed undervacuum and the resulting residue is purified by preparative HPLC on aC₁₈ column using a water:ACN:0.1% TFA gradient. The product fraction islyophilized to give the title compound.

[0898] PartC—DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt Conjugate

[0899] The product of Part B, above, and Et₃SiH are dissolved indegassed TFA and heated at 50° C. under nitrogen for 1 h. The solutionis concentrated and the resulting residue is purified by preparativeHPLC on a C₁₈ column using a water:ACN:0.1% TFA gradient. The productfraction is lyophilized to give the title compound.

Example 11DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-(4-(phosphonooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt Conjugate

[0900] The title compound is prepared by the same procedure describedfor Example 10 by substituting Boc-Tyr(PO₃H₂)-OSu for Boc-Cys(03H)-OSu.

Example 12DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-(4-(sulfooxy)phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Trifluoroacetate Salt Conjugate

[0901] The title compound is prepared by the same procedure describedfor Example 10 by substituting Boc-Tyr(SO₃H)-OSu for Boc-Cys(O₃H)-OSu.

Example 13DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Conjugate

[0902] Part A—Preparation ofBoc-Glu(aminoethyl-3,6-O-disulfo-β-D-galactopyranosyl)-OSu

[0903] A solution of Boc-Glu-OMe,aminoethyl-3,6-O-disulfo-β-D-galactopyranoside (as described in Tet.Lett. 1997, 53, 11937-11952), DIEA, and HBTU in anhydrous DMF is stirredat ambient temperatures under nitrogen for 18 h. The DMF is removedunder vacuum and the resulting residue is hydrolyzed using aqueous NaOH.The reaction solution is adjusted to pH 7 and purified by preparativeanion exchange chromatography using a resin such as DEAE Cellulose and aEt₃NH₂CO₃ gradient. The product fraction is treated with a cationexchange resin, sodium form, to give the intermediate carboxylic acid asthe sodium salt.

[0904] The above compound, N-hydroxysuccinimide, and DCC are dissolvedin anhydrous DMF and stirred at ambient temperatures under nitrogen for18 h. The DMF is removed under vacuum and the resulting residue ispurified by preparative anion exchange chromatography as above to givethe title compound as the triethylammonium salt.

[0905] PartB—DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ethyl-3,6-O-disulfo-β-D-galactopyranosyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Conjugate

[0906] The title compound is prepared by the same procedure describedfor Example 10 by substitutingBoc-Glu(aminoethyl-3,6-O-disulfo-β-D-galactopyranosyl)-OSu forBoc-Cys(03H)-OSu.

Example 14DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Bis(trifluoroacetate) Salt Conjugate

[0907] Part A—Preparation of Boc-Glu(6-amino-6-deoxy-β-cyclodextryl)-OMe

[0908] A solution of Boc-Glu-OMe, 6-amino-6-deoxy-β-cyclodextrin (asdescribed in J. Org. Chem. 1996, 61, 903-908), DIEA, and HBTU inanhydrous DMF is stirred at ambient temperatures under nitrogen for 18h. The DMF is removed under vacuum and the resulting residue is purifiedby preparative HPLC on a C₁₈ column using a water:ACN:0.1% TFA gradient.The product fraction is lyophilized to give the title compound.

[0909] Part B—Preparation of Boc-Glu(6-amino-6-deoxy-β-cyclodextryl)-OSu

[0910] The product of Part A, above, is hydrolyzed by stirring in amixture of LiOH, THF, and water at ambient temperatures under nitrogenfor 4 h. The THF is removed under vacuum and the resulting mixture isdiluted with water and adjusted to pH 3 using 0.1 N HCl. The mixture isextracted with EtOAc, and the combined extracts are dried (MgSO₄) andconcentrated. The resulting material is dissolved in anhydrous DMF alongwith N-hydroxysuccinimide, and DCC, and stirred at ambient temperaturesunder nitrogen for 18 h. The DMF is removed under vacuum and theresulting residue is purified by preparative HPLC on a C₁₈ column usinga water:ACN:0.1% TFA gradient. The product fraction is lyophilized togive the title compound.

[0911] PartC—DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(6-deoxy-β-cyclodextryl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Bis(trifluoroacetate) Salt Conjugate

[0912] The title compound is prepared by the same procedure describedfor Example 10 by substitutingBoc-Glu(6-amino-6-deoxy-β-cyclodextryl)-OSu for Boc-Cys(O₃H)-OSu.

Example 15DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Bis(trifluoroacetate) Salt Conjugate

[0913] Part A—Preparation of Boc-Glu(amino-ω-methoxypolyethyleneglycol)-OMe

[0914] A solution of Boc-Glu-OMe, amino-ω-methoxypolyethylene glycol,(MW=5,000), DIEA, and HBTU in anhydrous DMF is stirred at ambienttemperatures under nitrogen for 18 h. The DMF is removed under vacuumand the resulting residue is purified by preparative HPLC on a C₁₈column using a water:ACN:0.1% TFA gradient. The product fraction islyophilized to give the title compound.

[0915] Part B—Preparation of Boc-Glu(amino-ω-methoxypolyethyleneglycol)-OSu

[0916] The product of Part A, above, is hydrolyzed by stirring in amixture of LiOH, THF, and water at ambient temperatures under nitrogenfor 4 h. The THF is removed under vacuum and the resulting solution isadjusted to pH 7 using 0.1 N HCl. The solution is desalted using aSephadex PD-10 desalting column and the product eluant is lyophilized.The resulting material is dissolved in anhydrous DMF along withN-hydroxysuccinimide, and DCC, and stirred at ambient temperatures undernitrogen for 18 h. The DMF is removed under vacuum and the resultingresidue is purified by preparative HPLC on a C₁₈ column using awater:ACN:0.1% TFA gradient. The product fraction is lyophilized to givethe title compound.

[0917] PartC—DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-4-(N-(ω-methoxypolyethylene(5,000)glycoxyethyl)carbamoyl)butanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Bis(trifluoroacetate) Salt Conjugate

[0918] The title compound is prepared by the same procedure describedfor Example 10 by substituting Boc-Glu(amino-ω-methoxypolyethyleneglycol)-OSu for Boc-Cys(O₃H)-OSu.

Example 16 2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-Tetraaza-4,7,10-tris(carboxymethyl) cyclododecylacetylamino)-6-aminohexanoylamino) propoxy)ethoxy) ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo (3-hydroquinolyl))carbonylamino)propanoic AcidTris(trifluoroacetate) Salt

[0919] The title compound is prepared by the same procedure describedfor Example 10 by substituting Boc-Lys(Cbz)-OSu for Boc-Cys (03H)-OSu.

Example 172-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-Tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid Conjugate

[0920] A solution of bis(phosphonomethyl)glycine, DIEA, and HBTU inanhydrous DMF is stirred at ambient temperatures under nitrogen for 15min, and treated with the product of Example 16. Stirring is continuedfor 18 h and the DMF is removed under vacuum. The resulting residue ispurified by ion exchange chromatography.

Example 182-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid

[0921] The product of Example 10, Part A is dissolved in degassed TFAand stirred at ambient temperatures for 15 min. The solution isconcentrated under vacuum, and the resulting residue is dissolved in 50%ACN and lyophilized to remove the last traces of TFA. The material isdissolved in anhydrous DMF along with DIEA anddiethylenetriaminepentaacetic dianhydride. The resulting solution isstirred at ambient temperatures under nitrogen for 18 h. The DMF isremoved under vacuum and the resulting residue is purified bypreparative HPLC on a C₁₈ column using a water:ACN:0.1% TFA gradient.The product fraction is lyophilized to give the title compound.

[0922] The following procedure describe the synthesis ofradiopharmaceuticals of the present invention of the formula ^(99m)Tc(VnA)(tricine)(phosphine), in which (VnA) represents a vitronectinreceptor antagonist compound of the present invention bonded to the Tcthrough a diazenido (—N═N—) or hydrazido (═N—NH—) moiety. The diazenidoor hydrazido moiety results from the reaction of thehydrazinonicotinamido group, present either as the free hydrazine orprotected as a hydrazone, with the Tc-99m. The other two ligands in theTc coordination sphere are tricine and a phosphine.

Examples 19-23 Synthesis of Complexes[^(99m)Tc(HYNIC-VnA)(tricine)(TPPTS)].

[0923] To a lyophilized vial containing 4.84 mg TPPTS, 6.3 mg tricine,40 mg mannitol, succinic acid buffer, pH 4.8, and 0.1% Pluronic F-64surfactant, was added 1.1 mL sterile water for injection, 0.2 mL (20 μg)of the appropriate HYNIC-conjugated vitronectin antagonist (VnA) indeionized water or 50% aqueous ethanol, and 0.2 mL of ^(99m)TcO₄ ⁻ (50±5mCi) in saline. The reconstituted kit was heated in a 100° C. water bathfor 15 minutes, and was allowed to cool 10 minutes at room temperature.A sample of the reaction mixture was analyzed by HPLC. The RCP resultsare listed in the Table 1. HPLC Method Column: Zorbax C18, 25 cm × 4.6mm Flow rate: 1.0 mL/min Solvent A: 10 mM sodium phosphate buffer, pH6.0 Solvent B: 100% CH3CN Gradient A (Exs. 19, 20, 21) t (min) 0 20 2130 31 40 % Solvent B 0 25 75 75  0  0 Gradient B (Ex. 22) t (min) 0 2030 31 40 % Solvent B 0 50 50  0  0 Gradient C (Ex. 23) t (min) 0 20 2130 31 40 % Solvent B 10  30 75 75  0  0

[0924] TABLE 1 Analytical and Yield Data for ^(99m)Tc (VnA) (tricine)(TPPTS) Complexes Ret. Time Example No. Reagent No. (min) % Yield 19 18.8 73 20 3 17.2 81 21 4 17.6 68 22 6 11.7 79 23 7 16.4 52

Example 24 Synthesis of the In-111 Complex of3-((7-((Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicAcid

[0925] To a lead shielded and crimped autosampler vial was added 35 μgof the conjugate of Example 2 and 1.0 mg gentisic acid, sodium saltdissolved in 70 μL ammonium acetate buffer (0.4 M, pH 4.7) followed bythe addition of 2 mCi, 20 μL In-111 in 0.05 N HCl (specific activity: 17μg/mCi). The reaction mixture was heated at 70-80° C. for 60 min andanalyzed by HPLC and ITLC. The complex was formed in 93% yield and had aretention time of 19.6 min. HPLC Method Column: Zorbax Rx C18, 25 cm ×4.6 mm Column Temperature: Ambient Flow: 1.0 mL/min Solvent A: 10%Acetonitrile/0.1% TFA/H₂O Solvent B: Acetonitrile Detector: Sodiumiodide (NaI) radiometric probe Gradient t (min)  0 25 26 35 36 45 % B 1020 60 60 10 10

Examples 25-26 Synthesis of ¹⁷⁷Lu and ⁹⁰Y Complexes of3-((7-((Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicAcid.

[0926] To a clean sealed 5 mL vial was added 0.3 mL of a solution of thecomjugate of Example 2 (200 μg/mL in 0.5 M ammonium acetate buffer, pH6.9), followed by 0.05 mL of gentisic acid (sodium salt, 10 mg/mL in 0.5M ammonium acetate buffer, pH 6.9) solution, 0.3 mL of 0.5 M ammoniumacetate buffer (pH 6.9), and 0.010 mL of ¹⁷⁷LuC13 or ⁹⁰YC13 solution(1000 mCi/mL for ¹⁷⁷LuCl₃ and 500 mCi/mL for YC13) in 0.05 N HCl. Theresulting mixture was heated at 100° C. for 30 min. After cooling toroom temperature, a sample of the resulting solution was analyzed byradio-HPLC and ITLC. The radiolabeling yields were=90% (after correctionfor small amount of colloid) for both complex, and the retention timewas 19.2 min. HPLC Method Column: Zorbax C18, 25 cm × 4.6 mm Flow rate:1.0 mL/min Solvent A: 0.1% TFA aqueous solution Solvent B: 100% CH₃CN t(min)  0 20 25 30 31 40 % Solvent B 10 25 60 60 10 10

[0927] The instant thin layer chromatography (ITLC) method used GelmanSciences silica-gel strips and a 1:1 mixture of acetone and saline aseluant.

Example 27 Synthesis of ¹⁷⁷Lu Complex of the DOTA Conjugate of3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp-L-Asp)3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicAcid.

[0928] To a clean sealed 5 mL vial was added 0.5 mL of a solution of theconjugate of Example 8 (200 μg/mL in 0.5 M ammonium acetate buffer, pH6.9), followed by 0.05 mL of gentisic acid (sodium salt, 10 mg/mL in 0.5M ammonium acetate buffer, pH 6.9) solution, 0.25 mL of 0.5 M ammoniumacetate buffer (pH 6.9), and 0.05 mL of ¹⁷⁷LuCl₃ solution (200 mCi/mL)in 0.05 N HCl. The resulting mixture was heated at 100° C. for 30 min.After cooling to room temperature, a sample of the resulting solutionwas analyzed by radio-HPLC and ITLC. The radiolabeling yield was 75%(after correction for colloid), and the retention time was 20 min. HPLCMethod Column: Zorbax C18, 25 cm × 4.6 mm Flow rate: 1.0 mL/min SolventA: 10 mM phosphate buffer, pH = 6 Solvent B: 100% CH₃CN t (min) 0 20 2530 31 40 % Solvent B 0 20 50 50  0  0

Example 28 Synthesis of the Gadolinium Complex of2-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicAcid

[0929] The gadolinium complex of the conjugate of Example 18 is preparedaccording to the following procedure. 3-3.5 mg of the conjugate isdissolved in 2 mL 1 M ammonium acetate buffer at pH 7.0, and oneequivalent Gd(NO₃)₃ solution (0.02 M in water) is added to it. Thereaction mixture is allowed to stay at room temperature for 3-5 hoursand the product is isolated by HPLC. The fraction containing the complexis lyophilized and dissolved in 1 mL H₂O. The identity of the complex isconfirmed by mass spectroscopy.

Example 29 Synthesis of(2S)-2-[({2,6-Dimethyl-4-[3-(N-{2-[3-sulfo-2-(3-sulfo-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}propyl)propyl]ethyl}carbamoyl)propoxy]phenyl}sulfonyl)amino]-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid Trifluoroacetate Salt

[0930]

[0931] Part A—Preparation of Methyl(2S)-3-((tert-Butoxy)carbonylamino]-2-[({2,6-dimethyl-4-[3-(N-{2-[(phenylmethoxy)carbonylamino]ethyl}carbamoyl)propoxy]-phenyl}sulfonyl)amino]propanoate

[0932] A solution of the product of Example 3, Part D (369 mg, 0.756mmol), DIEA (0.52 mL, 3.0 mmol), and HBTU (315 mg, 0.832 mmol) inanhydrous DMF (14 mL) was stirred at ambient temperatures under nitrogenfor 5 min, and treated with benzyl N-(2-aminoethyl)carbamatehydrochloride (192 mg, 0.832 mmol), and stirred an additional 1 h. TheDMF was removed under vacuum, and the oily residue was taken up in EtOAc(150 mL), washed consecutively with 0.1 N HCl (40 mL), water (40 mL),and saturated NaCl (40 mL), dried (MgSO₄), and concentrated to give acolorless viscous oil. Flash chromatography on a 3×16 cm silica gelcolumn (EtOAc) gave the title compound as a colorless viscous oil (450mg, 89.6%). ¹H NMR (CDCl₃): δ 7.34-7.27 (m, 5H), 6.58 (s, 2H), 6.31 (bs,1H), 5.86 (bs, 1H), 5.36 (bs, 1H), 5.14-5.03 (m, 3H), 3.96 (t, J=6.0 Hz,2H), 3.88-3.83 (m, 1H), 3.56 (s, 3H), 3.47-3.25 (m, 6H), 2.59 (s, 6H),2.31 (t, J=6.9 Hz, 2H), 2.05 (p, J=6.6 Hz, 2H), 1.39 (s, 9H); ¹³C NMR(CDCl₃): δ 172.9, 170.5, 160.6, 157.3, 155.9, 141.8, 136.3, 128.5,128.2, 128.0, 116.6, 79.9, 66.9, 55.5, 52.8, 43.1, 40.9, 40.3, 32.4,28.2, 24.9, 23.3; MS: m/e 665.4 [M+H]; 687.3 [M+Na]; High Resolution MS:Calcd for C₃₁H₄₅N₄O₁₀S [M+H]: 665.2856, Found: 665.2883.

[0933] Part B—Preparation of Methyl(2S)-3-Amino-2-[({2,6-dimethyl-4-[3-(N-{2-[(phenylmethoxy)carbonylamino]ethyl}carbamoyl)propoxy]phenyl}sulfonyl)amino]propanoate Trifluoroacetate Salt

[0934] The product of Part A, above (420 mg, 0.632 mmol) was dissolvedin 25/75 DCM/TFA (20 mL) and allowed to stand at ambient temperaturesunder nitrogen for 10 min. The solution was concentrated, and theresulting viscous oil was dissolved in 50% ACN and lyophilized to givethe title compound as a colorless solid (437 mg, 102%). MS: m/e 565.3[M+H].

[0935] Part C—Preparation of Methyl(2S)-2-[({2,6-Dimethyl-4-[3-(N-{2-[(phenylmethoxy)carbonylamino]ethyl}carbamoyl)propoxy]phenyl}sulfonyl)amino]-3-{[1-methyl-4-oxo-7-([{1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoate

[0936] A solution of1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)hydroquinoline-3-carboxylicacid (702 mg, 1.30 mmol), DIEA (0.678 mL, 3.90 mmol), and HBTU (542 mg,1.43 mmol) in anhydrous DMF (60 mL) was stirred at ambient temperaturesunder nitrogen for 10 min, and treated with the product of Step B, above(881 mg, 1.30 mmol). After 75 min the DMF was removed under vacuum andthe resulting oil was purified by HPLC on a Vydac C-18 column (50×250mm) using a 1.24%/min gradient of 18 to 67.5% ACN containing 0.1% TFA ata flow rate of 80 mL/min. A peak eluting at 18.9 min was lyophilized togive unreacted1-methyl-4-oxo-7-(((1-(triphenylmethyl)imidazol-2-yl)amino)methyl)hydroquinoline-3-carboxylicacid (308 mg). The main product peak eluting at 23.7 min was lyophilizedto give the title compound as a colorless solid (890 mg, 63.0%). ¹H NMR(CDCl₃/D₂O): δ 8.50 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 7.70 (s, 1H),7.51-7.25 (m, 15H), 7.25-7.12 (m, 5H), 6.97 (s, 1H), 6.58 (d, J=2.3 Hz,1H), 6.34 (s, 2H), 6.32 (d, J=8.5 Hz, 1H), 5.09 (s, 2H), 4.65 (s, 2H),4.29-4.23 (m, 1H), 3.88 (s, 3H), 3.80-3.50 (m, 7H), 3.41-3.28 (m, 4H),2.61 (s, 6H), 2.26-2.11 (m, 2H), 1.92-1.76 (m, 2H); MS: m/e 1087.4[M+H]; 845.3 [M+H-Tr]; High Resolution MS: Calcd for C₆₀H₆₃N₈O₁₀S [M+H]1087.4388; found: 1087.440.

[0937] Part D—Preparation of Methyl(2S)-2-{[(4-{3-[N-(2-Aminoethyl)carbamoyl]propoxy}-2,6-dimethylphenyl)sulfonyl]amino}-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoate

[0938] Hydrogenolysis of the product of Part C, above (468 mg, 0.431mmol) was accomplished in MeOH (100 mL) over 10% Pd/C (95 mg) at 60 psifor 1 h. The catalyst was removed by filtration through Celite® and thefiltrate was concentrated to give the title compound as a pale amber oil(405 mg, 98.7%). MS: m/e 953.3 [M+H], 711.3 [M+H-Trityl].

[0939] Part E—Preparation of(2R)-N-(2-[4-(4-{[((1S)-1-(Methoxycarbonyl)-2-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}ethyl)amino]sulfonyl)-3,5-dimethylphenoxy)butanoylamino]ethyl}-2-[(tert-butoxy)carbonylamino]propanesulfonicAcid

[0940] A solution of the product of Part E, above (405 mg, 0.425 mmol),the p-nitrophenyl ester of Boc-L-cysteic acid (425 mg, 1.03 mmol), andDIEA (0.435 mL, 2.55 mmol) in anhydrous DMF (20 mL) was stirred atambient temperatures under nitrogen for 3 h. The DMF was removed undervacuum and the resulting oil was purified by HPLC on a Vydac C-18 column(50×250 mm) using a 1.12%/min gradient of 9 to 54% ACN containing 0.1%TFA at a flow rate of 80 mL/min. The main product peak eluting at 37.3min was lyophilized to give the title compound as a colorless solid (410mg, 80.2%). MS: m/e 1204.4 [M+H], 962.3 [M+H-Trt].

[0941] Part F—Preparation of(2R)-N-{2-[4-(4-{[((1S)-1-(Methoxycarbonyl)-2-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylaminoethyl)amino]sulfonyl}-3,5-dimethylphenoxy)butanoylamino]ethyl}-2-aminopropanesulfonicAcid

[0942] The product of Part E, above (410 mg, 0.341 mmol) was dissolvedin 50/50 TFA/DCM (20 mL) and allowed to react at ambient temperaturesfor 10 min. The solution was concentrated and the resulting amber oilwas dissolved in 50% ACN (50 mL) and lyophilized to give the titlecompound as a colorless solid (371 mg, 98.6%). MS: m/e 1104.4 [M+H],862.3 [M+H-Trt]; High Resolution MS: Calcd for C₅₅H₆₂N₉O₁₂S₂ [M+H]:1104.3959; Found: 1104.393.

[0943] Part G—Preparation of(2R)-N-[(1R)-1-(N-{2-[4-(4-{[((1S)-1-(Methoxycarbonyl)-2-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}ethyl)amino]sulfonyl}-3,5-dimethylphenoxy)butanoylamino]ethyl}carbamoyl)-2-sulfoethyl]-2-[(tert-butoxy)carbonylamino]propanesulfonicAcid

[0944] A solution of the product of Part F, above (110 mg, 0.100 mmol),the p-nitrophenyl ester of Boc-L-cysteic acid (82.4 mg, 0.200 mmol), andDIEA (0.104 mL, 0.600 mmol) in anhydrous DMF (5.0 mL) was stirred atambient temperatures under nitrogen for 48 h. The DMF was removed undervacuum and the resulting amber oil was purified by HPLC on a Vydac C-18column (50×250 mm) using a 1.12%/min gradient of 9 to 54% ACN containing0.1% TFA at a flow rate of 80 mL/min. The main product peak eluting at37.0 min was lyophilized to give the title compound as a colorless solid(96.0 mg, 70.9%). MS: m/e 1355.3 [M+H], 1113.3 [M-Trt+H], 1013.2[M-Trt-Boc+H].

[0945] Part H—Preparation of(2R)-N-[(1R)-1-(N-{2-[4-(4-{[((1S)-1-(Methoxycarbonyl)-2-{[I-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}ethyl)amino]sulfonyl}-3,5-dimethylphenoxy)butanoylamino]ethyl}carbamoyl)-2-sulfoethyl]-2-aminopropanesulfonicAcid

[0946] The product of Part G, above (21 mg, 0.0155 mmol) was dissolvedin 50/50 TFA/DCM (5.0 mL) and allowed to react at ambient temperaturesfor 10 min. The solution was concentrated and the residue was taken upin 50% ACN (15 mL) and lyophilized to give the title compound as acolorless solid (18.7 mg, 96.2%). MS: m/e 1255.3 [M+H], 1013.2[M+H-Trityl]; High Resolution MS: Calcd for C₅₈H₆₇N₁₀O₁₆S₃ [M+H]:1255.3899; Found: 1255.391.

[0947] Part I—Preparation of(2R)-N-[(1R)-1-(N-{2-[4-(4-{[((1S)-1-(Methoxycarbonyl)-2-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}ethyl)amino]sulfonyl}-3,5-dimethylphenoxy)butanoylamino]ethyl}carbamoyl)-2-sulfoethyl]-2-(2-{1,4,7,10-tetraaza-4,7,10-tris[(tert-butoxycarbonyl)methyl]cyclododecyl}acetylamino)propanesulfonic Acid

[0948] A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (30.0 mg, 0.0327 mmol)(as described in DM-7003), DIEA (0.034 mL,0.196 mmol), and HBTU (9.3 mg, 0.0245 mmol) in anhydrous DMF (1.5 mL)was stirred under nitrogen at ambient temperatures for 15 min andtreated with the product of Part H, above (18.7 mg, 0.0137 mmol). TheDMF was removed under vacuum after 75 min and the resulting amber oilwas purified by HPLC on a Vydac C-18 column (22×250 mm) using a 0.9%/mingradient of 22.5 to 58.5% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 26.1 min was lyophilized togive the title compound as acolorless fluffy solid (7.5 mg, 53%). MS:m/e 1809.7 [M+H].

[0949] Part J—Preparation of(2S)-2-[({2,6-Dimethyl-4-[3-(N-{2-[3-sulfo-2-(3-sulfo-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}propyl)propyl]ethyl}carbamoyl)propoxy]phenyl}sulfonyl)amino]-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)propanoicAcid Trifluoroacetate Salt

[0950] The product of Step I, above (7.5 mg, 0.0039 mmol) was dissolvedin a solution of peroxide-free THF (1.40 mL) and water (0.21 mL), andtreated with 3 N LiOH (0.14 mL). The mixture was stirred at ambienttemperatures under nitrogen for 1 h, and concentrated to dryness undervacuum. The resulting solid residue was dissolved in 95/5 TFA/Et₃SiH(2.0 mL) and heated at 70° C. under nitrogen for 1 h. The solution wasconcentrated under vacuum and the resulting solid residue was purifiedby HPLC on a Vydac C-18 column (22×250 mm) using a 0.90%/min gradient of0 to 27% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The mainproduct peak eluting at 20.5 min was lyophilized to give the titlecompound as a colorless fluffy solid (4.2 mg, 71.9%). MS: m/e 1385.3[M+H]; High Resolution MS: Calcd for C₅₄H₇₇N₁₄O₂₃S₃ [M+H]: 1385.4448;found: 1385.446.

Example 30 Synthesis ofDOTA/(2S)-2-{[(4-{3-[N-(2-{2-[(4S)-4-(N-{1-[N-(2-{4-[4-({[(1S)-1-Carboxy-2-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)ethyl]amino)sulfonyl)-3,5-dimethylphenoxy]-butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)-4-aminobutanoylamino]-3-sulfopropyl}ethyl)carbamoyl]propoxy)-2,6-dimethylphenyl)sulfonyl]amino}-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid Conjugate Bis(trifluoroacetate) Salt

[0951]

[0952] Part A—Preparation of Di-2,3,5,6-tetrafluorophenyl(2S)-2-[(tert-Butoxy) carbonylamino]pentane-1,5-diote

[0953] To a solution of Boc-L-Glu-OH (28.9 g, 117 mmol) in DMF (500 mL)at ambient temperatures and under nitrogen, was added a solution of2,3,5,6-tetrafluorophenol (48.2 g, 290 mmol) in DMF (50 mL). Afterstirring for 10 min, EDC (55.6 g, 290 mmol) was added and the mixturewas stirred for 96 h. The volatiles were removed under vacuum and theresidue was triturated with 0.1 N HCl (750 mL). To this mixture wasadded EtOAc (600 mL) and the layers were separated. The aqueous layerwas extracted with EtOAc (3×500 mL), and all EtOAc extracts werecombined, washed consecutively with water (300 mL) and saturated NaCl(300 mL), dried (MgSO₃), and concentrated to give a tan solid (62 g).The tan solid was washed with ACN to give the title compound (45.5 g,73.0%) in purified form. MS: m/e 566.0 [M+Na].

[0954] Part B—Preparation of(2R)-2-[4-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-2-({7-[([1-(Triphenylmethyl)imidazol-2-yl]amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)-1-(methoxycarbonyl)ethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)(4S)-4-[(tert-butoxy)carbonylamino]-butanoylamino]-N-(2-{4-[4-({[(1S)-2-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-1-(methoxycarbonyl)ethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)propanesulfonicAcid

[0955] A solution of the product of Example 29, Part F (130 mg, 0.118mmol), the product of Part A, above (27.2 mg, 0.050 mmol), and DIEA(0.070 mL, 0.40 mmol) in anhydrous DMF (4.0 mL) was stirred at ambienttemperatures under nitrogen for 29 h. The DMF was removed under vacuumand the resulting amber oil was purified by HPLC on a Vydac C-18 column(50×250 mm) using a 0.90%/min gradient of 22.5 to 58.5% ACN containing0.1% TFA at a flow rate of 80 mL/min. The main product peak eluting at35.7 min was lyophilized to give the title compound as a colorlessfluffy solid (108 mg, 89.3%). MS: m/e 2419.6 [M+H], 1210.4 [M+2H].

[0956] Part C—Preparation of(2R)-2-[4-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-2-({7-[([1-(Triphenylmethyl)imidazol-2-yl]amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)-1-(methoxycarbonyl)ethyl]amino)sulfonyl)-3,5-dimethylphenoxy]butanoylamino)ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)(4S)-4-aminobutanoylamino]-N-(2-{4-[4-({[(1S)-2-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-(methoxycarbonyl)ethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)propanesulfonicAcid

[0957] The product of Part B, above (107 mg, 0.0442 mmol) was dissolvedin 50/50 TFA/DCM (5.0 mL) and allowed to react at ambient temperaturesunder nitrogen for 10 min. The solution was concentrated and theresulting amber oil was dissolved in 50% ACN (25 mL) and lyophilized togive the title compound as a pale yellow solid (105 mg, 98.0%). MS: m/e1159.9 [M+2H], 1039.4 [M+2H-Trt].

[0958] Part D—Preparation of DOTA tri-t-ButylEster/(2R)-2-[4-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-2-([7-[([1-(Triphenylmethyl)imidazol-2-yl]amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-(methoxycarbonyl)ethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)(4S)-4-aminobutanoylamino]-N-(2-{4-[4-({[(1S)-2-([7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-(methoxycarbonyl)ethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)propanesulfonicAcid Conjugate

[0959] A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (31.6 mg, 0.0346 mmol)(as described in DM-7003), DIEA (0.072 mL,0.416 mmol), and HBTU (9.8 mg, 0.026 mmol) in anhydrous DMF (1.8 mL) wasstirred under nitrogen at ambient temperatures for 15 min and treatedwith the product of Part C, above (40.0 mg, 0.0173 mmol). The DMF wasremoved under vacuum after 90 min and the resulting pale yellow oil waspurified by HPLC on a Vydac C-18 column (50×250 mm) using a 1.01%/mingradient of 22.5 to 63.0% ACN containing 0.1% TFA at a flow rate of 80mL/min. The main product peak eluting at 27.6 min was lyophilized togive the title compound as a colorless solid (29.0 mg, 62.4%). MS: m/e1437.6 [M+2H], 1316.6 [M+2H-Trt].

[0960] Part E—Preparation ofDOTA/(2S)-2-{[(4-{3-[N-(2-{2-[(4S)-4-(N-{1-[N-(2-{4-[4-({[(1S)-1-Carboxy-2-((7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)ethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)-4-aminobutanoylamino]-3-sulfopropyl}ethyl)carbamoyl]propoxy)-2,6-dimethylphenyl)sulfonyl]amino}-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid Conjugate Bis(trifluoroacetate) Salt

[0961] A mixture of the product of Part D, above (30.0 mg, 0.0104 mmol),peroxide-free THF (3.2 mL), water (0.485 mL), and 3 N LiOH (0.320 mL,0.96 mmol) was stirred at ambient temperatures under nitrogen for 2 h.The solution was concentrated under vacuum and the resulting solidresidue was dissolved in 95/5 TFA/Et₃SiH (5.0 mL). The solution washeated at 70° C. under nitrogen for 1 h and concentrated under vacuum.The resulting oily solid was purified by HPLC on a Vydac C-18 column(22×250 mm) using a 0.90%/min gradient of 0 to 27% ACN containing 0.1%TFA at a flow rate of 20 mL/min. The main product peak eluting at 27.8min was lyophilized to give the title compound as a cololess fluffysolid (12.8 mg, 48.5%). MS: m/e 1096.8 [M+2H], 731.8 [M+3H]; HighResolution MS: Calcd for C₉₁H₁₂₂N₂₃O₃₃S₄ [M+H]: 2192.7458; Found:2192.741.

Example 31 Synthesis of2-[({4-[3-(N-{2-[(2R)-2-((2R)-3-Sulfo-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}propyl)-3-sulfopropyl]ethyl}carbamoyl)propoxy]-2,6-dimethylphenyl}sulfonyl)amino](2S)-3-((7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid Trifluoroacetate Salt

[0962]

[0963] Part A—Preparation of2-({[4-(3-{N-[2-((2R)-2-Amino-3-sulfopropyl)ethyl]carbamoyl}propoxy)-2,6-dimethylphenyl]-sulfonyl}amino)(2S)-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylaminopropanoic Acid

[0964] A mixture of the product of Example 29, Part F (125 mg, 0.113mmol), peroxide-free THF (3.8 mL), water (0.57 mL), and 3 N LiOH (0.38mL, 1.13 mmol) was stirred at ambient temperatures under nitrogen for 1h. The mixture was adjusted to pH 1 using 1 N HCl (0.70 mL) andconcentrated to dryness under vacuum. The resulting solid was purifiedby HPLC on a Vydac C-18 column (50×250 mm) using a 0.90%/min gradient of18 to 54% ACN containing 0.1% TFA at a flow rate of 80 mL/min. The mainproduct peak eluting at 21.0 min was lyophilized to give the titlecompound as a colorless solid (96.0 mg, 77.9%). MS: m/e 1090.3 [M+H],848.2 [M+H-Trt]; High Resolution MS: Calcd for C₅₄H₆₀N₉O₁₂S₂ [M+H]:1090.3808; Found: 1090.381.

[0965] Part B—Preparation of2-({[4-(3-{N-[2-((2R)-2-{(2R)-2-[(tert-Butoxy)carbonylamino]-3-sulfopropyl}-3-sulfopropyl)ethyl]carbamoyl}propoxy)-2,6-dimethylphenyl]sulfonyl}amino)(2S)-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoicAcid

[0966] A solution of Boc-L-cysteic acid (37.0 mg, 0.128 mmol), DIEA(0.040 mL, 0.228 mmol), and PyBOP (53.0 mg, 0.102 mmol) in anhydrous DMF(1.0 mL) was stirred at ambient temperatures under nitrogen for 15 min,and added to a solution of the product of Part A, above (93.0 mg, 0.0854mmol) and DIEA (0.045 mL, 0.256 mmol) in anhydrous DMF (3.0 mL). Theresulting solution was stirred at ambient temperatures under nitrogenfor 1.5 h and concentrated to a viscous amber oil. Purification by HPLCon a Vydac C-18 column (50×250 mm) using a 0.68%/min gradient of 18 to45% ACN containing 0.1% TFA at a flow rate of 80 mL/min. The mainproduct peak eluting at 36.4 min was lyophilized to give the titlecompound as a colorless solid (94.0 mg, 82.1%). MS: m/e 1341.2 [M+H],1099.1 [M+H-Trt], 999.1 [M+H-Trt-Boc].

[0967] Part C—Preparation of2-{[(4-{3-[N-(2-{(2R)-2-[(2R)-3-Sulfo-2-(2-{1,4,7,10-tetraaza-4,7,10-tris[(tert-butoxycarbonyl)methyl]cyclododecyl}acetylamino)propyl]-3-sulfopropyl}ethyl)carbamoyl]propoxy}-2,6-dimethylphenyl)sulfonyl]amino}(2S)-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoicAcid

[0968] A solution of the product of Part B, above (90.0 mg, 0.0672 mmol)in 50/50 TFA/DCM (10.0 mL) was allowed to react at ambient temperaturesunder nitrogen for 10 min and concentrated under vacuum to give theintermediate amine as an amber oil. MS: m/e 1241.3 [M+H], 999.3[M+H-Trt]; High Resolution MS: Calcd for C₅₇H₆₅N₁₀O₁₆S₃ [M+H]:1241.3742; Found: 1241.375.

[0969] A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (123 mg, 0.134 mmol)(as described in DM-7003), DIEA (0.092 mL,0.538 mmol), and PyBOP (52.4 mg, 0.101 mmol) in anhydrous DMF (1.5 mL)was stirred under nitrogen at ambient temperatures for 15 min, and addedto a solution of the free amine produced above (90.0 mg, 0.0672 mmol)and DIEA (0.046 mL, 0.269 mmol) in anhydrous DMF (1.5 mL). The DMF wasremoved under vacuum after 1 h and the resulting amber oil was purifiedby HPLC on a Vydac C-18 column (50×250 mm) using a 0.288%/min gradientof 30.6 to 45% ACN containing 0.1% TFA at a flow rate of 80 mL/min. Themain product peak eluting at 25.8 min was lyophilized to give the titlecompound as a colorless solid (92.0 mg, 76.3%). MS: m/e 1795.6 [M+H],1553.5 [M+H-Trt]; High Resolution MS: Calcd for C₈₅H₁₁₅N₁₄O₂₃S₃ [M+H]:1795.7422; Found: 1795.744.

[0970] Part D—Preparation of2-[({4-[3-(N-{2-[(2R)-2-((2R)-3-Sulfo-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}propyl)-3-sulfopropyl]ethyl}carbamoyl)propoxy]-2,6-dimethylphenyl}sulfonyl)amino](2S)-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid Trifluoroacetate Salt

[0971] A solution of the product of Part C, above (89.0 mg, 0.0496 mmol)in 97/3 TFA/Et₃SiH (10.0 mL) was heated at 70° C. under nitrogen for 30min and concentrated under vacuum. The resulting oily solid was purifiedby HPLC on a Vydac C-18 column (50×250 mm) using a 0.45%/min gradient of4.5 to 22.5% ACN containing 0.1% TFA at a flow rate of 80 mL/min. Themain product peak eluting at 19.5 min was lyophilized to givesteochemically pure title compound as a colorless fluffy solid (65.0 mg,87.5%). MS: m/e 1385.4 [M+H].

Example 32 Alternative Synthesis of Intermediate2-({[4-(3-{N-[2-((2R)-2-Amino-3-sulfopropyl)ethyl]carbamoyl}propoxy)-2,6-dimethylphenyl]sulfonyl}amino)(2S)-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoicAcid

[0972]

[0973] Part A—Preparation of(2S)-2-{[(4-{3-[N-(2-Aminoethyl)carbamoyl]propoxy}-2,6-dimethylphenyl)sulfonyl]amino}-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoicAcid

[0974] A mixture of the product of Example 29, Part D (956 mg, 1.004mmol), peroxide-free THF (35 mL), water (5.3 mL), and 3 N LiOH (3.53 mL,10.6 mmol) was stirred at ambient temperatures under nitrogen for 1 h,and adjusted to pH 5-6 using 1 N HCl (10 mL). The THF was removed undervacuum causing a gummy yellow solid to precipitate. The water layer wasremoved by decantation and the solid was washed with water (15 mL). Thesolid was dried under vacuum to give the title compound as a dry yellowsolid

[0975] Part B—Preparation of2-{[(4-{3-[N-(2-{(2R)-2-[(tert-Butoxy)carbonylamino]-3-sulfopropyl}ethyl)carbamoyl]-propoxy}-2,6-dimethylphenyl)sulfonyl]amino}(2S)-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoicAcid

[0976] A solution of Boc-L-cysteic acid (175 mg, 0.60 mmol), DIEA (0.208mL, 1.20 mmol), and PyBOP (250 mg, 0.480 mmol) in anhydrous DMF (5.0 mL)was stirred at ambient temperatures under nitrogen for 17 min, and addedto a solution of the product of Part A, above (375 mg, 0.400 mmol) andDIEA (0.070 mL, 0.400 mmol) in anhydrous DMF (4.0 mL). The resultingsolution was stirred at ambient temperatures under nitrogen for 45 minand concentrated under vacuum to give an amber oil. Purification by PLCon a Vydac C-18 column (50×250 mm) using a 0.292%/min gradient of 31.5to 43.2% ACN containing 0.1% TFA at a flow rate of 80 mL/min. The mainproduct peak eluting at 22.0 min was lyophilized to give the titlecompound as a colorless solid (430 mg, 90.4%). MS: m/e 1190.3 [M+H],948.3 [M+H-Trt].

[0977] Part C—Preparation of2-({[4-(3-{N-[2-((2R)-2-Amino-3-sulfopropyl)ethyl]carbamoylpropoxy)-2,6-dimethylphenyl]-sulfonyl}amino)(2S)-3-{[1-methyl-4-oxo-7-({[1-(triphenylmethyl)imidazol-2-yl]amino}methyl)(3-hydroquinolyl)]carbonylamino}propanoicAcid

[0978] A solution of the product of Part B, above (430 mg, 0.362 mmol)in 50/50 TFA/DCM (15 mL) was allowed to react at ambient temperaturesunder nitrogen for 10 min and concentrated under vacuum. The resultingamber oil was taken up in 50% ACN (50 mL) and lyophilized to give thetitle compound as a pale yellow solid (398 mg, 100%). MS: m/e 1090.3[M+H], 848.2 [M+H-Trt].

Example 33 Synthesis ofDOTA/2-{[(4-{3-[N-(2-{(2R)-2-[(2R)-2-(4-{N-[(1R)-1-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-1-Carboxy-2-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-carboxyethyl]amino}-sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)-2-sulfoethyl]carbamoyl}(2S)-2-aminobutanoylamino)-3-sulfopropyl]-3-sulfopropyl}ethyl)carbamoyl]propoxy)-2,6-dimethylphenyl)sulfonyl]amino}(2S)-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid Conjugate

[0979]

[0980] Part A—Preparation of2-{[(4-[3-[N-(2-{(2R)-2-[(2R)-2-(4-[N-[(1R)-1-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-1-Carboxy-2-({7-[({1-(triphenylmethyl)imidazol-2-yl)amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-carboxyethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)-2-sulfoethyl]carbamoyl}(2S)-2-[(tert-butoxy)carbonylamino]butanoylamino)-3-sulfopropyl]-3-sulfopropyl)ethyl)carbamoyl]propoxy}-2,6-dimethylphenyl)sulfonyl]amino}(2S)-3-({7-[({1-(triphenylmethyl)imidazol-2-yl}amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)propanoicAcid

[0981] A solution of the product of the first half of Example 31, Part C(136 mg, 0.110 mmol), DIEA (0.076 mL, 0.44 mmol), and the product ofExample 30, Part A (26.2 mg, 0.050 mmol) in anhydrous DMF (3.0 mL) wasstirred at ambient temperatures under nitrogen for 7 h. The DMF wasremoved under vacuum and the viscous amber oil was purified by HPLC on aVydac C-18 column (50×250 mm) using a 0.45%/min gradient of 27 to 45%ACN, followed by a 0.72% gradient of 45-63% ACN containing 0.1% TFA at aflow rate of 80 mL/min. The main product peak eluting at 75.2 min waslyophilized to give the title compound as a colorless solid (129 mg,47.9%). MS: m/e 1347.3 [M+2H].

[0982] Part B—Preparation of DOTA tri-t-Butyl Ester Conjugate of2-{[(4-[3-(N-(2-{(2R)-2-[(2R)-2-(4-(N-[(1R)-1-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-1-Carboxy-2-({7-[([1-(triphenylmethyl)imidazol-2-yl}amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-carboxyethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)-2-sulfoethyl]carbamoyl}(2S)-2-aminobutanoylamino)-3-sulfopropyl]-3-sulfopropyl}-ethyl)carbamoyl]propoxy}-2,6-dimethylphenyl)sulfonyl]-amino}(2S)-3-({7-[({1-(triphenylmethyl)imidazol-2-yl)amino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}-carbonylamino)propanoicAcid

[0983] The product of Part A, above (34.0 mg, 0.0126 mmol) was dissolvedin 50/50 TFA/DCM (12 mL) and allowed to react at ambient temperaturesunder nitrogen for 10 min.

[0984] The solution was concentrated and the resulting amber oil wasdried under vacuum. A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (23.1 mg, 0.0253 mmol), DIEA (0.020 mL, 0.115 mmol), and PyBOP (9.8mg, 0.019 mmol) in anhydrous DMF (2.0 mL) was stirred under nitrogen atambient temperatures for 15 min, and added to a solution of the productfrom the deprotection reaction, above and DIEA (0.020 mL, 0.115 mmol) inanhydrous DMF (2.0 mL). The DMF was removed under vacuum after 2 h, andthe resulting residue was purified by HPLC on a Vydac C-18 column(50×250 mm) using a 0.45%/min gradient of 27 to 49.5% ACN containing0.1% TFA at a flow rate of 80 mL/min. The main product peak eluting at43.8 min was lyophilized to give the title compound as a colorless solid(16.0 mg, 40.4%). MS: m/e 1574.8 [M+2H], 1453.7 [M+2H-Trt], 1332.2[M+2H-2Trt].

[0985] Part C—Preparation ofDOTA/2-{[(4-{3-[N-(2-{(2R)-2-[(2R)-2-(4-{N-[(1R)-1-(N-{(1R)-1-[N-(2-{4-[4-({[(1S)-1-Carboxy-2-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)-1-carboxyethyl]amino}sulfonyl)-3,5-dimethylphenoxy]butanoylamino}ethyl)carbamoyl]-2-sulfoethyl}carbamoyl)-2-sulfoethyl]carbamoyl}(2S)-2-aminobutanoylamino)-3-sulfopropyl]-3-sulfopropyl}-ethyl)carbamoyl]propoxy}-2,6-dimethylphenyl)sulfonyl]-amino)(2S)-3-({7-[(imidazol-2-ylamino)methyl]-1-methyl-4-oxo(3-hydroquinolyl)}carbonylamino)propanoicAcid Conjugate

[0986] The product of Part B, above (14.0 mg, 0.00445 mmol) wasdissolved in 95/5 TFA/Et₃SiH (8.0 mL) and heated at 70° C. undernitrogen for 1 h. The solution was concentrated under vacuum and theresulting yellow solid was purified by HPLC on a Vydac C-18 column(22×250 mm) using a 0.9%/min gradient of 0 to 27% ACN containing 0.1%TFA at a flow rate of 20 mL/min. The main product peak eluting at 24.5min was lyophilized to give the title compound as a colorless solid (8.2mg, 73.9%). MS: m/e 1247.7 [M+2H].

Example 34 Synthesis of(2S)-3-{[7-[(Imidazol-2-ylamino)methyl]-4-oxo-1-(3-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}propyl)(3-hydroquinolyl)]carbonylamino}-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino)propanoicAcid Tris(trifluoroacetate) Salt

[0987]

[0988] Part A—Preparation of(2S)-3-({7-[(Imidazol-2-ylamino)methyl]-4-oxo-1-[3-(2-{1,4,7,10-tetraaza-4,7,10-tris[(tert-butoxycarbonyl)methyl]cyclododecyl}acetylamino)propyl](3-hydroquinolyl)}carbonylamino)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Tris(trifluoroacetate) Salt

[0989] A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (89 mg, 0.0974 mmol)(as described in DM-7003), DIEA (0.103 mL,0.607 mmol), and HBTU (28.0 mg, 0.0735 mmol) in anhydrous DMF (1.0 mL)was stirred under nitrogen at ambient temperatures for 15 min andtreated with a solution of the product of Example 4, Part H (30.0 mg,0.049 mmol) in anhydrous DMF (1.0 mL). The DMF was removed under vacuumafter 3 h and the residue was purified by HPLC on a Vydac C-18 column(22×250 mm) using a 1.08%/min gradient of 18 to 72% ACN containing 0.1%TFA at a flow rate of 20 mL/min. The main product peak eluting at 17.5min was lyophilized to give the title compound as a colorless solid(48.0 mg, 65.0%). MS: m/e 1164.7 [M+H].

[0990] Part B—Preparation of(2S)-3-{[7-[(Imidazol-2-ylamino)methyl]-4-oxo-1-(3-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}propyl)(3-hydroquinolyl)]carbonylamino}-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Tris(trifluoroacetate) Salt

[0991] A solution of the product of Part A, above (48.0 mg, 0.0375 mmol)in 95/5 TFA/Et₃SiH (2.1 mL) was stirred at 50° C. under nitrogen for 2h. The solution was concentrated under vacuum and the oily residue waspurified by HPLC on a Vydac C-18 column (22×250 mm) using a 1.2%/mingradient of 0 to 36% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 18.6 min was lyophilized togive the title compound as a colorless solid (25.7 mg, 51.2%). MS: m/e996.5 [M+H]; High Resolution MS: Calcd for C₄₅H₆₂N₁₁O₁₃S [M+H]:996.4249; Found: 996.4278.

Example 35 Synthesis of3-({1-[3-((2R)-3-Sulfo-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]-acetylamino}propyl)propyl]-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)}carbonylamino)(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Bis(trifluoroacetate) Salt

[0992]

[0993] Part A—Preparation of3-{[1-(3-{(2R)-2-[(tert-Butoxy)carbonylamino]-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid

[0994] A solution of the product of Example 4, Part H (105 mg, 0.125mmol), the N-hydroxysuccinimide ester of Boc-Cysteic acid (as describedin Liebigs Ann. Chem. 1979, 776-783)(146 mg, 0.467 mmol), and DIEA(0.120 mL, 0.69 mmol) in anhydrous DMF (1.5 mL) was stirred at ambienttemperatures under nitrogen for 24 h. The DMF was removed under vacuumand the resulting solid residue was purified by HPLC on a Vydac C-18column (22×250 mm) using a 0.68%/min gradient of 9 to 36% ACN containing0.1% TFA at a flow rate of 20 mL/min. The main product peak eluting at30.3 min was lyophilized to give the title compound as a colorless solid(73.0 mg, 67.9%). MS: m/e 861.3 [M+H].

[0995] Part B—Preparation of3-({1-[3-((2R)-2-Amino-3-sulfopropyl)propyl]-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl))carbonylamino)(2S)-2-([(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Trifluoroacetate Salt

[0996] The product of Part B, above (70.0 mg, 0.0814 mmol) was dissolvedin 2:1 DCM/TFA (1.5 ML) and allowed to react at ambient temperaturesunder nitrogen for 30 min. The solution was concentrated under vacuumand the amber oil was dissolved in 50% ACN (25 mL) and lyophilized togive the title compound as a colorless solid (70.8 mg, 99.5%). MS: m/e761.2 [M+H]; High Resolution MS: Calcd for C₃₂H₄₁N₈O₁₀S₂ [M+H]:761.2387; Found: 761.2393.

[0997] Part C—Preparation of3-[(1-{3-[(2R)-3-Sulfo-2-(2-{1,4,7,10-tetraaza-4,7,10-tris[(tert-butoxycarbonyl)methyl]cyclododecyl}acetylamino)propyl]propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl))carbonylamino](2S)-2-([(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Bis(trifluoroacetate) Salt

[0998] A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (20.8 mg, 0.0228 mmol)(as described in DM-7003), DIEA (0.006 mL,0.034 mmol), and HBTU (6.5 mg, 0.0171 mmol) in anhydrous DMF (0.5 mL)was stirred under nitrogen at ambient temperatures for 5 min and treatedwith a solution of the product of Part B, above (10.0 mg, 0.0114 mmol)and DIEA (0.006 mL, 0.034 mmol) in anhydrous DMF (0.5 mL). Stirring wascontinued at ambient temperatures for 24 h, and the reaction was dilutedwith water (3.0 mL), treated with concentrated ammonium hydroxide (0.003mL), and stirred an additional 10 min. The solution was adjusted to pH 3using 0.1 N HCl (6.0 mL) and diluted further with 10% ACN (5.5 mL). Thissolution was purified directly by HPLC on a Vydac C-18 column (22×250mm) using a 0.68%/min gradient of 9 to 36% ACN containing 0.1% TFA at aflow rate of 20 mL/min. The main product peak eluting at 36.0 min waslyophilized to give the title compound as a colorless solid (12.0 mg,68.3%). MS: m/e 1315.6 [M+H].

[0999] Part D—Preparation of3-({1-[3-((2R)-3-Sulfo-2-t2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]-acetylamino}propyl)propyl]-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)}carbonylamino)(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Bis(trifluoroacetate) Salt

[1000] A solution of the product of Part C, above (12.0 mg, 0.00778mmol) in 95/5 TFA/Et₃SiH (1.0 mL) was stirred at ambient temperaturesunder nitrogen for 18 h. The solution was concentrated under vacuum andthe oily residue was purified by HPLC on a Vydac C-18 column (22×250 mm)using a 1.2%/min gradient of 0 to 36% ACN containing 0.1% TFA at a flowrate of 20 mL/min. The main product peak eluting at 21.1 min waslyophilized to give the title compound as a colorless solid (8.1 mg,75.7%). MS: m/e 1147.3 [M+H]; High Resolution MS: Calcd forC₄₈H₆₇N₁₂O₁₇S₂ [M+H]: 1147.4189; Found: 1147.418.

Example 36 Synthesis of3-{[1-(3-{2-[(6-{[(1E)-1-Aza-2-(2-sulfophenyl)vinyl]amino}(3-pyridyl))carbonylamino](2R)-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid

[1001]

[1002] A solution of the product of Example 35, Part B (10.0 mg, 0.0101mmol), DIEA (0.007 mL, 0.040 mmol), and2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (5.3 mg, 0.0120 mmol) in anhydrous DMF (0.5 mL) was allowed tostand at ambient temperatures under a nitrogen atmosphere for 48 h.Additional2-(2-aza-2-((5-((2,5-dioxopyrrolidinyl)carbonyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid (2.0 mg, 0.00455 mmol) was added and stirring was continued anadditional 48 h. The DMF was removed under vacuum and the residue waspurified by HPLC on a Vydac C-18 column (22×250 mm) using a 0.9%/mingradient of 0 to 36% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 30.0 min was lyophilized togive the title compound as a colorless solid (2.5 mg, 23.3%). MS: m/e1064.3 [M+H]; High Resolution MS: Calcd for C₄₅H₅₀N₁₁O₁₄S₃ [M+H]:1064.27005; Found: 1064.272.

Example 37 Synthesis of3-{[1-(3-{(2R)-2-[4-(N-{(1R)-1-[N-(3-{3-[N-((2S)-2-Carboxy-2-{[(2,4,6-trimethylphenyl)sulfonyl]-amino}ethyl)carbamoyl]-7-[(imidazol-2-ylamino)methyl]-4-oxohydroquinolyl}propyl)carbamoyl]-2-sulfoethyl}-carbamoyl)(2S)-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino)butanoylamino]-3-sulfopropyl)propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Bis(trifluoroacetate) Salt

[1003]

[1004] Part A—Preparation of3-([1-(3-{(2R)-2-[4-(N-{(1R)-1-[N-(3-[3-[N-((2S)-2-Carboxy-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl)carbamoyl]-7-[(imidazol-2-ylamino)methyl]-4-oxohydroquinolyl}propyl)carbamoyl]-2-sulfoethyl}carbamoyl)(2S)-2-[(tert-butoxy)carbonylamino]-butanoylamino]-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid

[1005] A solution of the product of Example 35, Part B (38.0 mg, 0.0434mmol), DIEA (0.015 mL, 0.0869 mmol), and the product of Example 30, PartA (10.9 mg, 0.0202 mmol) in anhydrous DMF (1.0 mL) was stirred atambient temperatures under nitrogen for 48 h. The DMF was removed undervacuum and the amber oil was purified by HPLC on a Vydac C-18 column(22×250 mm) using a 0.68%/min gradient of 9 to 36% ACN containing 0.1%TFA at a flow rate of 20 mL/min. The main product peak eluting at 36.1min was lyophilized to give the title compound as a colorless solid(13.5 mg, 38.6%). MS: m/e 1732.4 [M+H], 1632.2 [M+H-Boc].

[1006] Part B—Preparation of3-{[1-(3-{(2R)-2-[4-(N-{(1R)-1-[N-(3-{3-[N-((2S)-2-Carboxy-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl)carbamoyl]-7-[(imidazol-2-ylamino)methyl]-4-oxohydroquinolyl}propyl)carbamoyl]-2-sulfoethyl}carbamoyl)(2S)-2-aminobutanoylamino]-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Trifluoroacetate Salt

[1007] The product of Part A, above (13.5 mg, 0.00779 mmol) wasdissolved in 50/50 TFA/DCM (1.0 mL) and allowed to react at ambienttemperatures under nitrogen for 45 min. The solution was concentratedunder vacuum to give the title compound as a pale amber oil. MS: m/e1633.3 [M+H].

[1008] Part C—Preparation of3-{[1-(3-{(2R)-2-[4-(N-{(1R)-1-[N-(3-{3-[N-((2S)-2-Carboxy-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl)carbamoyl]-7-[(imidazol-2-ylamino)methyl]-4-oxohydroquinolyl}propyl)carbamoyl]-2-sulfoethyl}carbamoyl)(2S)-2-{2-[1,4,7,10-tetraaza-4,7,10-tris[(tert-butoxycarbonyl)methyl]cyclododecyl]acetylamino}-butanoylamino]-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}-(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Bis(trifluoroacetate) Salt

[1009] A solution of2-(1,4,7,10-tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)aceticacid (15.0 mg, 0.0164 mmol)(as described in DM-7003), DIEA (0.004 mL),and HBTU (4.7 mg, 0.0124 mmol) in anhydrous DMF (0.5 mL) was stirredunder nitrogen at ambient temperatures for 8 min and treated with asolution of the product of Part B, above (0.00779 mmol) and DIEA (0.004mL) in anhydrous DMF (0.5 mL). The solution was stirred at ambienttemperatures for 24 h, treated with 0.1 N NaOH (0.33 mL), stirred anadditional 5 min, and adjusted to pH 3 with 0.1 N HCl (0.60 mL). Thissolution was diluted with water (4.5 mL) and purified directly by HPLCon a Vydac C-18 column (22×250 mm) using a 1.01%/min gradient of 9 to49.5% ACN containing 0.1% TFA at a flow rate of 20 mL/min. The mainproduct peak eluting at 26.7 min was lyophilized to give the titlecompound as a colorless solid (7.0 mg, 37.2%). MS: m/e 1094.4 [M+2H];High Resolution MS: Calcd for C₉₇H₁₃₆N₂₁O₂₉S₄ [M+H]: 2186.8696; Found:2186.867.

[1010] Part D—Preparation of3-{[1-(3-{(2R)-2-[4-(N-{(1R)-1-[N-(3-{3-[N-((2S)-2-Carboxy-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}ethyl)carbamoyl]-7-[(imidazol-2-ylamino)methyl]-4-oxohydroquinolyl}propyl)carbamoyl]-2-sulfoethyl}carbamoyl)(2S)-2-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acetylamino}butanoylamino]-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicAcid Bis(trifluoroacetate) Salt

[1011] A solution of the product of Step C, above (7.0 mg, 0.00290 mmol)in 95/5 TFA/Et₃SiH (1.0 mL) was heated to reflux under nitrogen for 3 h.The solution was concentrated under vacuum and the oily residue waspurified by HPLC on a Vydac C-18 column (22×250 mm) using a 1.2%/mingradient of 0 to 36% ACN containing 0.1% TFA at a flow rate of 20mL/min. The main product peak eluting at 26.5 min was lyophilized togive the title compound as a colorless solid (4.5 mg, 66.1%). HighResolution MS: Calcd for C₈₅H₁₁₂N₂ O₂₉S₄ [M+H]: 2018.6818; Found:2018.683.

Example 38

[1012] Synthesis of the In-111 Complex of the Conjugate Example 29

[1013] To a shielded and crimped 2 cc autosampler vial was added 70 μgof the conjugate of Example 29 dissolved in 140 μl 0.5 M ammoniumacetate buffer (pH 4.8) followed by the addition of 2 mg gentisic acidsodium salt and 2.6 mCi (7 μl) In-111 in 0.05M HCl. The reaction mixture(specific activity was heated at 85° C. for 20 minutes and analyzed byHPLC. Yield: 87.9% (total for the two isomers); Ret. Time: 12.5, 13.1min. HPLC Method Column: Zorbax Rx C18, 25 cm × 4.6 mm ColumnTemperature: Ambient Flow: 1.0 ml/min Solvent A: 10 mM ammonium acetateSolvent B: Acetonitrile Detector: IN-US β-ram, and UV at 220 nmwavelength. Gradient t (min) 0 25 26 35 36 45 % B 7  7 60 60  7  7

Example 39

[1014] Synthesis of the In-111 Complex of the Conjugate Example 30

[1015] To a lead shielded and crimped 2 cc autosampler vial was added120 μg of the conjugate of Example 30 dissolved in 240 μL ammoniumacetate buffer (0.5 M, pH 4.7) followed by the addition of 2 mg ofgentisic acid (sodium salt) dissolved in 20 μL of H₂O, and 2.3 mCi, (10μL) In-111 (NEN) in 0.05 N HCl (specific activity: 52 μg/mCi). Thereaction mixture was heated at 100° C. for 20 min and analyzed by HPLC.Yield: 94.7% (total for the two isomers), Ret. Time: 16.6 and 17.3 min.HPLC Method Column: Zorbax Rx C18, 25 cm × 4.6 mm Column Temperature:Ambient Flow: 1.0 ml/min Solvent A: 10 mM ammonium acetate Solvent B:Acetonitrile Detector: IN-US β-ram, and UV at 220 nm wavelength.Gradient t (min)  0 25 26 35 36 45 % B 10 15 60 60 10 10

Example 40

[1016] Synthesis of the In-111 Complex of the Conjugate Example 31

[1017] To a shielded and crimped 2 cc autosampler vial was added 70 μgof the conjugate of Example 31 dissolved in 140 μl 0.5 M ammoniumacetate buffer (pH 4.8) followed by the addition of 2 mg gentisic acidsodium salt and 2.6 mCi (7 μl) In-111 in 0.05M HCl. The reaction mixture(specific activity was heated at 85° C. for 20 minutes and analyzed byHPLC. Yield: 92.2%; Ret. Time: 12.9 min. HPLC Method Column: Zorbax RxC18, 25 cm × 4.6 mm Column Temperature: Ambient Flow: 1.0 ml/min SolventA: 10 mM ammonium acetate Solvent B: Acetonitrile Detector: IN-US β-ram,and UV at 220 nm wavelength. Gradient t (min) 0 25 26 35 36 45 % B 7  760 60  7  7

Example 41

[1018] Synthesis of the In-111 Complex of the Conjugate Example 33

[1019] To a shielded and crimped 2 cc autosampler vial was added 107 μgof the conjugate of Example 33 dissolved in 140 μl 0.5 M ammoniumacetate buffer (pH 4.8) followed by the addition of 2 mg gentisic acidsodium salt and 2.6 mCi (7 μl) In-111 in 0.05M HCl. The reaction mixture(specific activity was heated at 85° C. for 20 minutes and analyzed byHPLC. Yield: 77.9%; Ret. Time: 17.8 min. HPLC Method Column: Zorbax RxC18, 25 cm × 4.6 mm Column Temperature: Ambient Flow: 1.0 ml/min SolventA: 10 mM ammonium acetate Solvent B: Acetonitrile Detector: IN-US β-ram,and UV at 220 nm wavelength. Gradient t (min) 0 25 26 35 36 45 % B 9 1160 60  9  9

Example 42

[1020] Synthesis of the In-111 Complex of the Conjugate Example 34

[1021] To a lead shielded and crimped autosampler vial was added 25 μgof the conjugate of Example 34 and 1.0 mg gentisic acid, sodium saltdissolved in 50 μL ammonium acetate buffer (0.4 M, pH 4.7) followed bythe addition of 1.2 mCi, (5 μL) In-111 in 0.05 N HCl (specific activity:21 μg/mCi). The reaction mixture was heated at 80° C. for 45 min andanalyzed by HPLC and ITLC. 93.5% yield by HPLC, Ret. Time: 16.7 min.HPLC Method Column: Zorbax Rx C18, 25 cm × 4.6 mm Column Temperature:Ambient Flow: 1.0 ml/min Solvent A: 25 mM sodium phosphate buffer at pH6 Solvent B: Acetonitrile Detector: Sodium iodide (NaI) radiometricprobe, and UV at 220 nm wavelength. Gradient t (min)  0 25 26 35 36 45 %B 10 20 60 60 10 10

Example 43

[1022] Synthesis of the In-111 Complex of the Conjugate Example 35

[1023] To a lead shielded and crimped 1 cc autosampler vial was added40-50 μg of the conjugate of Example 35 dissolved in 100 μL ammoniumcitrate buffer (0.4 M, pH 4.7) followed by the addition of 2 mCi, (5 μL)In-111 in 0.05 N HCl (specific activity: 25 μg/mCi). The reactionmixture was heated at 90-100 C for 30 min and analyzed by HPLC. Yield:95%; Ret. Time 12.5 min. HPLC Method Column: Zorbax Rx C18, 25 cm × 4.6mm Column Temperature: Ambient Flow: 1.0 ml/min Solvent A: 25 mM sodiumphosphate buffer at pH 6 Solvent B: Acetonitrile Detector: Sodium iodide(NaI) radiometric probe, and UV at 220 nm wavelength. Gradient t (min) 0 25 26 35 36 45 % B 10 20 60 60 10 10

Example 44

[1024] Synthesis of the In-111 Complex of the Conjugate Example 37

[1025] To a lead shielded and crimped 2 cc autosampler vial was added150 μg of the conjugate of Example 37 dissolved in 300 μL ammoniumcitrate buffer (0.3 M, pH 4.8) followed by the addition of 4.5 mCi, (25μL) In-111 (NEN) in 0.05 N HCl (specific activity: 33 μg/mCi). Thereaction mixture was heated at 100° C. for 20 min and analyzed by HPLC.RCP: 80%, Ret. Time: 21 min. HPLC Method Column: Zorbax Rx C18, 25 cm ×4.6 mm Column Temperature: Ambient Flow: 1.0 ml/min Solvent A: 25 mMsodium phosphate buffer at pH 6 Solvent B: Acetonitrile Detector: Sodiumiodide (NaI) radiometric probe, and UV at 220 nm wavelength. Gradient t(min)  0 25 26 35 36 45 % B 17 19 60 60 17 17

Examples 45-51

[1026] Synthesis of Y-90 and Lu-177 Complexes of the Conjugates ofExamples 30, 31, 34, 35 and 37

[1027] To a clean sealed 5 mL vial was added 0.5-1.0 mL of theappropriate conjugate solution (200 ug/mL in 0.5 M ammonium acetatebuffer, pH 7.0-8.0), followed by 0.05 mL of sodium gentisate (10 mg/mLin 0.5 M ammonium acetate buffer, pH 7.0-8.0) solution, and 10-40 μL of⁹YC13 or ¹⁷⁷ LuCl₃ solution (10-20 mCi) in 0.05 N HCl. The 3 reactionmixture was heated at 100° C. for 5-10 min. After cooling to roomtemperature, a sample of the resulting solution was analyzed by HPLC andby ITLC. Ret. Complex Conjugate Time HPLC Ex # Isotope Ex. # (min) %Yield Method 45 Y-90 30 14.0, 90 D 16.0 46 Y-90 31 14.0 90.5 F 47 Lu-17731 13.0 85 D 48 Y-90 34 8.0 81.9 A 49 Y-90 35 16.0 89 B 50 Y-90 37 8.283.5 B 51 Lu-177 37 14.0 70 G

[1028] HPLC Method A: The HPLC method using a reverse phase C₁₈ Zorbaxcolumn (4.6 mm×25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min witha gradient mobile phase from 85% A (25 mM pH 6.0 phosphate buffer) and15% B (acetonitrile) to 75% A and 25% B at 20 min.

[1029] HPLC Method B: The HPLC method using a reverse phase C₁₈ Zorbaxcolumn (4.6 mm×25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min witha gradient mobile phase from 90% A (25 mM pH 6.0 phosphate buffer) and10% B (acetonitrile) to 80% A and 20% B at 20 min.

[1030] HPLC Method D: The HPLC method using a reverse phase C₁₈ Zorbaxcolumn (4.6 mm×25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min witha gradient mobile phase from 87% A (25 mM pH 6.0 phosphate buffer) and13% B (acetonitrile) to 86% A and 14% B at 20 min.

[1031] HPLC Method F: The HPLC method using a reverse phase C₁₈ Zorbaxcolumn (4.6 mm×25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min witha gradient mobile phase from 92% A (25 mM ammonium acetate buffer,pH=6.8) and 8% B (acetonitrile) to 90% A and 10% B at 20 min.

[1032] HPLC Method G: The HPLC method using a reverse phase C₁₈ Zorbaxcolumn (4.6 mm×25 cm, 80 Å pore size) at a flow rate of 1.0 mL/min withan isocratic mobile phase of 87% A (25 mM ammonium acetate buffer, pH6.8) and 13% B (acetonitrile) from 0 to 20 min.

Example 52

[1033] Synthesis of ^(99m)Tc(3-{[1-(3-{2-[(6-(diazenido)(3-pyridyl))carbonylamino](2R)-3-sulfopropyl)propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicacid) (tricine)(TPPTS)

[1034] To a lyophilized vial containing 4.84 mg TPPTS, 6.3 mg tricine,40 mg mannitol, succinic acid buffer, pH 4.8, and 0.1% Pluronic F-64surfactant, was added 1.1 mL sterile water for injection, 0.2 mL (20 μg)of the the conjugate of Example 36 in deionized water or 50% aqueousethanol, and 0.2 mL of ^(99m)TcO₄ ⁻ (50±5 mCi) in saline. Thereconstituted kit was heated in a 100° C. water bath for 15 minutes, andwas allowed to cool 10 minutes at room temperature. A sample of thereaction mixture was analyzed by HPLC. The yield was 89.0% and theretention time 12.8, 13.2 min (2 isomers).

[1035] HPLC Method

[1036] Column: Zorbax C₁₈, 25 cm×4.6 mm

[1037] Flow rate: 1.0 mL/min

[1038] Solvent A: 10 mM sodium phosphate buffer, pH 6.0

[1039] Solvent B: 100% CH₃CN

[1040] Gradient 0-25% B over 20 min.

[1041] Utility

[1042] The pharmaceuticals of the present invention are useful forimaging angiogenic tumor vasculature, therapeutic cardiovascularangiogenesis, and cardiac pathologies associated with the expression ofvitronectin receptors in a patient or for treating cancer in a patient.The radiopharmaceuticals of the present invention comprised of a gammaray or positron emitting isotope are useful for imaging of pathologicalprocesses involving angiogenic neovasculature, including cancer,diabetic retinopathy, macular degeneration, restenosis of blood vesselsafter angioplasty, and wound healing, as well as atherosclerotic plaque,myocardial reperfusion injury, and myocardial ischemia, stunning orinfarction. The radiopharmaceuticals of the present invention comprisedof a beta, alpha or Auger electron emitting isotope are useful fortreatment of pathological processes involving angiogenic neovasculature,by delivering a cytotoxic dose of radiation to the locus of theangiogenic neovasculature. The treatment of cancer is affected by thesystemic administration of the radiopharmaceuticals resulting in acytotoxic radiation dose to tumors.

[1043] The compounds of the present invention comprised of one or moreparamagnetic metal ions selected from gadolinium, dysprosium, iron, andmanganese, are useful as contrast agents for magnetic resonance imaging(MRI) of pathological processes involving angiogenic neovasculature, aswell as atherosclerotic plaque, myocardial reperfusion injury, andmyocardial ischemia, stunning or infarction.

[1044] The compounds of the present invention comprised of one or moreheavy atoms with atomic number of 20 or greater are useful as X-raycontrast agents for X-ray imaging of pathological processes involvingangiogenic neovasculature, as well as atherosclerotic plaque, myocardialreperfusion injury, and myocardial ischemia, stunning or infarction.

[1045] The compounds of the present invention comprised of an echogenicgas containing surfactant microsphere are useful as ultrasound contrastagents for sonography of pathological processes involving angiogenicneovasculature, as well as atherosclerotic plaque, myocardialreperfusion injury, and myocardial ischemia, stunning or infarction.

[1046] Representative compounds of the present invention were tested inthe following in vitro assays and in vivo models and were found to beactive.

[1047] Immobilized Human Placental α_(v)β₃ Receptor Assay

[1048] The assay conditions were developed and validated using[I-125]vitronectin. Assay validation included Scatchard format analysis(n=3) where receptor number (Bmax) and Kd (affinity) were determined.Assay format is such that compounds are preliminarily screened at 10 and100 nM final concentrations prior to IC50 determination. Three standards(vitronectin, anti-α_(v)β₃ antibody, LM609, and anti-α_(v)β₅, PlF₆) andfive reference peptides have been evaluated for IC50 determination.Briefly, the method involves immobilizing previously isolated receptorsin 96 well plates and incubating overnight. The receptors were isolatedfrom normal, fresh, non-infectious (HIV, hepatitis B and C, syphilis,and HTLV free) human placenta. The tissue was lysed and tissue debrisremoved via centrifugation. The lysate was filtered. The receptors wereisolated by affinity chromatography using the immobilized α_(v)β₃antibody. The plates are then washed 3× with wash buffer. Blockingbuffer is added and plates incubated for 120 minutes at roomtemperature. During this time compounds to be tested and[I-125]vitronectin are premixed in a reservoir plate. Blocking buffer isremoved and compound mixture pipetted. Competition is carried out for 60minutes at room temperature. Unbound material is then removed and wellsare separated and counted via gamma scintillation.

[1049] Oncomouse® Imaging

[1050] The study involves the use of the c-Neu Oncomouse® and FVB micesimultaneously as controls. The mice are anesthetized with sodiumpentobarbital and injected with approximately 0.5 mCi ofradiopharmaceutical. Prior to injection, the tumor locations on eachOncomouse® are recorded and tumor size measured using calipers. Theanimals are positioned on the camera head so as to image the anterior orposterior of the animals. 5 Minute dynamic images are acquired seriallyover 2 hours using a 256×256 matrix and a zoom of 2×. Upon completion ofthe study, the images are evaluated by circumscribing the tumor as thetarget region of interest (ROI) and a background site in the neck areabelow the carotid salivary glands.

[1051] This model can also be used to assess the effectiveness of theradiopharmaceuticals of the present invention comprised of a beta, alphaor Auger electron emitting isotope. The radiopharmaceuticals areadministered in appropriate amounts and the uptake in the tumors can bequantified either non-invasively by imaging for those isotopes with acoincident imageable gamma emission, or by excision of the tumors andcounting the amount of radioactivity present by standard techniques. Thetherapeutic effect of the radiopharmaceuticals can be assessed bymonitoring the rate of growth of the tumors in control mice versus thosein the mice administered the radiopharmaceuticals of the presentinvention.

[1052] This model can also be used to assess the compounds of thepresent invention comprised of paramagnetic metals as MRI contrastagents. After administration of the appropriate amount of theparamagnetic compounds, the whole animal can be placed in a commerciallyavailable magnetic resonance imager to image the tumors. Theeffectiveness of the contrast agents can be readily seen by comparisonto the images obtain from animals that are not administered a contrastagent.

[1053] This model can also be used to assess the compounds of thepresent invention comprised of heavy atoms as X-ray contrast agents.After administration of the appropriate amount of the X-ray absorbingcompounds, the whole animal can be placed in a commercially availableX-ray imager to image the tumors. The effectiveness of the contrastagents can be readily seen by comparison to the images obtain fromanimals that are not administered a contrast agent.

[1054] This model can also be used to assess the compounds of thepresent invention comprised of an echogenic gas containing surfactantmicrosphere as ultrasound contrast agents. After administration of theappropriate amount of the echogenic compounds, the tumors in the animalcan be imaging using an ultrasound probe held proximate to the tumors.The effectiveness of the contrast agents can be readily seen bycomparison to the images obtain from animals that are not administered acontrast agent.

[1055] Rabbit Matrigel Model

[1056] This model was adapted from a matrigel model intended for thestudy of angiogenesis in mice. Matrigel (Becton & Dickinson, USA) is abasement membrane rich in laminin, collagen IV, entactin, HSPG and othergrowth factors. When combined with growth factors such as bFGF

[1057] [500 ng/ml] or VEGF [2 ug/ml] and injected subcutaneously intothe mid-abdominal region of the mice, it solidifies into a gel andstimulates angiogenesis at the site of injection within 4-8 days. In therabbit model, New Zealand White rabbits (2.5-3.0 kg) are injected with2.0 ml of matrigel, plus 1 jug bFGF and 4 μg VEGF. Theradiopharmaceutical is then injected 7 days later and the imagesobtained.

[1058] This model can also be used to assess the effectiveness of theradiopharmaceuticals of the present invention comprised of a beta, alphaor Auger electron emitting isotope. The radiopharmaceuticals areadministered in appropriate amounts and the uptake at the angiogenicsites can be quantified either non-invasively by imaging for thoseisotopes with a coincident imageable gamma emission, or by excision ofthe angiogenic sites and counting the amount of radioactivity present bystandard techniques. The therapeutic effect of the radiopharmaceuticalscan be assessed by monitoring the rate of growth of the angiogenic sitesin control rabbits versus those in the rabbits administered theradiopharmaceuticals of the present invention.

[1059] This model can also be used to assess the compounds of thepresent invention comprised of paramagnetic metals as MRI contrastagents. After administration of the appropriate amount of theparamagnetic compounds, the whole animal can be placed in a commerciallyavailable magnetic resonance imager to image the angiogenic sites. Theeffectiveness of the contrast agents can be readily seen by comparisonto the images obtain from animals that are not administered a contrastagent.

[1060] This model can also be used to assess the compounds of thepresent invention comprised of heavy atoms as X-ray contrast agents.After administration of the appropriate amount of the X-ray absorbingcompounds, the whole animal can be placed in a commercially availableX-ray imager to image the angiogenic sites. The effectiveness of thecontrast agents can be readily seen by comparison to the images obtainfrom animals that are not administered a contrast agent.

[1061] This model can also be used to assess the compounds of thepresent invention comprised of an echogenic gas containing surfactantmicrosphere as ultrasound contrast agents. After administration of theappropriate amount of the echogenic compounds, the angiogenic sites inthe animal can be imaging using an ultrasound probe held proximate tothe tumors. The effectiveness of the contrast agents can be readily seenby comparison to the images obtain from animals that are notadministered a contrast agent.

[1062] Canine Spontaneous Tumor Model

[1063] Adult dogs with spontaneous mammary tumors were sedated withxylazine (20 mg/kg)/atropine (1 ml/kg). Upon sedation the animals wereintubated using ketamine (5 mg/kg)/diazepam (0.25 mg/kg) for fullanethesia. Chemical restraint was continued with ketamine (3mg/kg)/xylazine (6 mg/kg) titrating as necessary. If required theanimals were ventilated with room air via an endotrachael tube (12strokes/min, 25 ml/kg) during the study. Peripheral veins werecatheterized using 20G I.V. catheters, one to serve as an infusion portfor compound while the other for exfusion of blood samples. Heart rateand EKG were monitored using a cardiotachometer (Biotech, Grass Quincy,MA) triggered from a lead II electrocardiogram generated by limb leads.Blood samples are generally taken at 10 minutes (control), end ofinfusion, (1 minute), 15 min, 30 min, 60 min, 90 min, and 120 min forwhole blood cell number and counting. Radiopharmaceutical dose was 300μCi/kg adminitered as an i.v. bolus with saline flush. Parameters weremonitored continuously on a polygraph recorder (Model 7E Grass) at apaper speed of 10 mm/min or 10 mm/sec.

[1064] Imaging of the laterals were for 2 hours with a 256×256 matrix,no zoom, 5 minute dynamic images. A known source is placed in the imagefield (20-90 μCi) to evaluate region of interest (ROI) uptake. Imageswere also acquired 24 hours post injection to determine retention of thecompound in the tumor. The uptake is determined by taking the fractionof the total counts in an inscribed area for ROI/source and multiplyingthe known μCi. The result is μCi for the ROI.

[1065] This model can also be used to assess the effectiveness of theradiopharmaceuticals of the present invention comprised of a beta, alphaor Auger electron emitting isotope. The radiopharmaceuticals areadministered in appropriate amounts and the uptake in the tumors can bequantified either non-invasively by imaging for those isotopes with acoincident imageable gamma emission, or by excision of the tumors andcounting the amount of radioactivity present by standard techniques. Thetherapeutic effect of the radiopharmaceuticals can be assessed bymonitoring the size of the tumors over time.

[1066] This model can also be used to assess the compounds of thepresent invention comprised of paramagnetic metals as MRI contrastagents. After administration of the appropriate amount of theparamagnetic compounds, the whole animal can be placed in a commerciallyavailable magnetic resonance imager to image the tumors. Theeffectiveness of the contrast agents can be readily seen by comparisonto the images obtain from animals that are not administered a contrastagent.

[1067] This model can also be used to assess the compounds of thepresent invention comprised of heavy atoms as X-ray contrast agents.After administration of the appropriate amount of the X-ray absorbingcompounds, the whole animal can be placed in a commercially availableX-ray imager to image the tumors. The effectiveness of the contrastagents can be readily seen by comparison to the images obtain fromanimals that are not administered a contrast agent.

[1068] This model can also be used to assess the compounds of thepresent invention comprised of an echogenic gas containing surfactantmicrosphere as ultrasound contrast agents. After administration of theappropriate amount of the echogenic compounds, the tumors in the animalcan be imaging using an ultrasound probe held proximate to the tumors.The effectiveness of the contrast agents can be readily seen bycomparison to the images obtain from animals that are not administered acontrast agent.

[1069] Cardiovascular disease models that can be used to assess thediagnostic radiopharmaceuticals, magnetic resonance, X-ray andultrasound contrast agents of the present invention are reviewed in J.Nucl. Cardiol., 1998, 5, 167-83. There are several well establishedrabbit models of atherosclerosis; one model produces predominantlyproliferating smooth muscle cells by balloon deendothelialization ofinfradiaphragmatic abdominal aorta to simulate restenotic lesions;another model that produces simulated advanced human atheroscleroticplaque by balloon deendothelialization followed by a high cholesteroldiet. A model of congestive heart failure is described in Am. J.Physiol., 1998, 274, H1516-23. In general, Yorkshire pigs are randomlyassigned to undergo 3 wks of rapid atrial pacing at 240 beats/min. or tobe sham controls. The pigs are chronically instrumented to measure leftventricular function in the conscious state. The pigs are anesthetized.

[1070] A shielded stimulating electrode is sutured onto the left atrium,connected to a modified programmable pace maker and buried in asubcutaneous pocket. The pericardium is closed loosely, the thoracotomyis closed, and the pleural space is evacuated of air. After a recoveryperiod of 7-10 days, the pacemaker is activated in the animals selectedto undergo chronic rapid pacing. The animals are sedated, the pacemakeris deactivated (pacing groups only. After a 30 min stabilization period,indexes of LV function and geometry are determined (by echocardiographyas a control) by injecting the radiolabeled compound. Forbiodistribution, the animals are anesthetized, the heart extirpate andthe LV apex and midventricular regions are evaluated.

[1071] A rat model of reversible coronary occlusion and reperfusion isdescribed in McNulty et al., J. Am. Physiol., 1996, H2283-9.

[1072] Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is described below:
 1. A compound, comprising: atargeting moiety and a chelator, wherein the targeting moiety is boundto the chelator, is a quinolone nonpeptide, and binds to a receptor thatis upregulated during angiogenesis and the compound has 0-1 linkinggroups between the targeting moiety and chelator.
 2. A compoundaccording to claim 1, wherein the receptor is the integrin α_(v)β₃ orα_(v)β₅ and the compound is of the formula: (Q)_(d)—L_(n)—C_(h) or(Q)_(d)—L_(n)—(C_(h))_(d′) wherein, Q is a compound of Formula (II):

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein: R^(1e) is selected from:

A^(e) is —CH₂— or —N(R^(10e))—; A^(1e) and B^(e) are independently —CH₂—or —N(R^(10e))—; D^(e) is —N(R^(10e))— or —S—; E^(e)-F^(e) is—C(R^(2e))═C(R^(3e))— or —C(R^(2e))₂C(R^(3e))₂—; J^(e) is —C(R^(2e))— or—N—; K^(e), L^(e) and M^(e) are independently —C(R^(2e))— or—C(R^(3e))—; R^(2e) and R^(3e) are independently selected from: H, C₁-C₄alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl,and aryl substituted with 0-4 R^(7e), alternatively, when R^(2e) andR^(3e) are substituents on adjacent atoms, they can be taken togetherwith the carbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being substituted with 0-2groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃and NO₂; R^(2ae) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl,C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl,aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;R^(7e) is selected from: H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl,aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e),SO₂NR^(10e)R^(11e), OR^(10e), and N(R^(11e))R^(12e); U^(e) is selectedfrom: —(CH₂)_(n) ^(e)—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —(CH₂)_(n)^(e)N(R¹²)(CH₂)_(m) ^(e)—, —NH(CH₂)_(n) ^(e)—, —(CH₂)_(n)^(e)C(═O)(CH₂)_(m) ^(e)—, —(CH₂)_(n) ^(e)S(O)_(p) ^(e) (CH₂)_(m) ^(e)—,—(CH₂)_(n) ^(e)NHNH (CH₂)_(m) ^(e)—, —N(R^(10e))C(═O)—,—NHC(═O)(CH₂)_(n) ^(e)—, —C(═O)N(R^(10e))—, and —N(R^(10e))S(O)_(p)^(e)—; G^(e) is N or CR^(19e); W^(e) is —C(═O)—N(R^(10e))—(C₁-C₃alkylene)-, in which the alkylene group is substituted by R^(8e) and byR^(9e): R^(8e) and R^(9e) are independently selected from: H,CO₂R^(18be), C(═O)R^(18be), CONR¹⁷R^(18be), C₁-C₁₀ alkyl substitutedwith 0-1 R^(6e), C₂-C₁₀ alkenyl substituted with 0-1 R^(6e), C₂-C₁₀alkynyl substituted with 0-1 R^(6e), C₃-C₈ cycloalkyl substituted with0-1 R^(6e), C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e), (C₁-C₁₀alkyl)carbonyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, phenyl substituted with0-3 R⁶, naphthyl substituted with 0-3 R^(6e), a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 R^(7e),C₁-C₁₀ alkoxy substituted with 0-2 R^(7e), hydroxy, nitro,—N(R^(10e))R^(11e), —N(R^(16e))R^(17e), aryl(C₀-C₆ alkyl)carbonyl,aryl(C₃-C₆ alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18ae)R^(20e),SO₂R^(1e)ae, and SO₂NR^(18ae)R^(20e), providing that any of the abovealkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted orsubstituted independently with 1-2 R^(7e); R^(6e) is selected from: H,C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be), C(═O)R^(18be),CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e),NR^(10e)C(═O) R^(10e), NR^(10e)C(═O) OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p)R^(11e), SO₂NR^(10e)R^(11e), arylsubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂, aryl(C₁-C₄ alkyl)-, said arylbeing substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me, and —NMe₂, and a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 R^(7e);R^(10e) is selected from: H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R^(6e); R^(11e) is selected from: H, hydroxy, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, C₁-C₆alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl (C-C₄ alkyl)-,aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀ alkyl substituted with0-2 R^(4e); R^(4e) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, (C₁-C₁₀ alkyl)carbonyl, aryl,heteroaryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl)-, whereinsaid aryl or heteroaryl groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂, alternatively, when R^(10e) and R^(11e)are both substituents on the same nitrogen atom (as in —NR^(10e)R^(11e))they may be taken together with the nitrogen atom to which they areattached to form a heterocycle selected from: 3-azabicyclononyl,1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl,1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl,thiazolidinyl, and 1-piperazinyl; said heterocycle being substitutedwith 0-3 groups selected from: C₁-C₆ alkyl, aryl, heteroaryl, aryl(C₁-C₄alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆alkoxy)carbonyl, aryl(C₁-C₄ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, andarylsulfonyl; R^(12e) is selected from: H, C₁-C₆ alkyl, triphenylmethyl,methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl,(C₁-C₆ alkyl) carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl,heteroarylcarbonyl, aryl (C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl,arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl, wherein said arylgroups are substituted with 0-2 substituents selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R^(16e)is selected from: —C(═O)OR^(18ae), —C(═O)R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), —C(═O)NHC(═O) R^(18be), —C(═O)NHC(═O)OR^(18ae),—C(═O)NHSO₂NHR^(18be), —SO₂R^(18ae), —SO₂N(R^(18be))₂, and—SO₂NHC(═O)OR^(18be); R^(17e) is selected from: H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl, aryl(C₁-C₆ alkyl)-,and heteroaryl(C₁-C₆ alkyl); R^(18ae) is selected from: C₁-C₈ alkyloptionally substituted with a bond to L_(n), C₃-C₁₁ cycloalkyloptionally substituted with a bond to L_(n), aryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆ alkyl)-optionally substituted with a bond to L_(n), (C₁-C₆ alkyl)heteroaryloptionally substituted with a bond to L_(n), biaryl(C₁-C₆ alkyl)optionally substituted with a bond to L_(n), heteroaryl optionallysubstituted with a bond to L_(n), phenyl substituted with 3-4 R^(19e)and optionally substituted with a bond to L_(n), naphthyl substitutedwith 0-4 R^(19e) and optionally substituted with a bond to L_(n), and abond to L_(n), wherein said aryl or heteroaryl groups are optionallysubstituted with 0-4 R^(19e); R^(18be) is H or R^(18ae); R^(19e) isselected from: H, halogen, CF₃, CO₂H, CN, NO₂, NR^(11e)R^(12e), OCF₃,C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, C₁-C₄alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—, heteroaryl, andheteroaryl-SO₂—, wherein said aryl and heteroaryl groups are substitutedwith 0-4 groups selected from hydrogen, halogen, CF₃, C₁-C₃ alkyl, andC₁-C₃ alkoxy; R^(20e) is selected from: hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy (C₁-C₂ alkyl) oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)-; R^(21e) is selected from: C₁-C₈alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R^(7e);R^(22e) is selected from: —C(═O)—R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), —C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae) and—C(═O)NHSO₂NHR^(18be); Y^(e) is selected from: —COR^(20e), —SO₃H, —PO₃H,—CONHNHSO₂CF₃, —CONHSO₂R^(18ae), —CONHSO₂NHR^(18be), —NHCOCF₃,—NHCONHSO₂R^(18ae), —NHSO₂R^(18ae), —OPO₃H₂, —OSO₃H, —PO₃H₂,—SO₂NHCOR^(18ae), —SO₂NHCO₂R^(18ae),

m^(e) is 0-2; n^(e) is 0-4; p^(e) is 0-2; r^(e) is 0-2; with thefollowing proviso: n^(e) and m^(e) are chosen such that the number ofatoms connecting R^(1e) and Y^(e) is in the range of 8-14; d is selectedfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; d′ is 1-100; L_(n) is a linkinggroup having the formula:(W)_(h)—(CR⁶R⁷)_(g))_(x)—(Z)_(k)—((CR^(6a)R^(7a))_(g′), —(W)_(h′))_(x′);W is independently selected at each occurrence from the group: O, S, NH,NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O, OC(═O), NHC(═S)NH,NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″),(CH₂CH₂CH₂O)_(t), and (aa)_(t′); aa is independently at each occurrencean amino acid; Z is selected from the group: aryl substituted with 0-3R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁰, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁰; R⁶, R^(6a), R⁷,R^(7a), and R⁸ are independently selected at each occurrence from thegroup: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkyl substituted with 0-3 R¹⁰,aryl substituted with 0-3 R¹⁰, benzyl substituted with 0-3 R¹⁰, andC₁-C₅ alkoxy substituted with 0-3 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹,NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to C_(h); R¹⁰ is independentlyselected at each occurrence from the group: a bond to C_(h), COOR¹¹,C(═O)NHR¹¹, NHC(═O)R¹¹, OH, NHR¹¹, SO₃H, PO₃H, —OPO₃H₂, —OSO₃H, arylsubstituted with 0-3 R¹¹, C₁₅ alkyl substituted with 0-1 R¹², C₁₋₅alkoxy substituted with 0-1 R¹², and a 5-10 membered heterocyclic ringsystem containing 1-4 heteroatoms independently selected from N, S, andO and substituted with 0-3 R¹¹; R¹¹ is independently selected at eachoccurrence from the group: H, alkyl substituted with 0-1 R¹², arylsubstituted with 0-1 R¹², a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-1 R¹², C₃-10 cycloalkyl substituted with 0-1 R¹²,polyalkylene glycol substituted with 0-1 R¹², carbohydrate substitutedwith 0-1 R¹², cyclodextrin substituted with 0-1 R¹², amino acidsubstituted with 0-1 R¹², polycarboxyalkyl substituted with 0-1 R¹²,polyazaalkyl substituted with 0-1 R¹², peptide substituted with 0-1 R¹²,wherein the peptide is comprised of 2-10 amino acids,3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and abond to C_(h); R¹² is a bond to C_(h); k is selected from 0, 1, and 2; his selected from 0, 1, and 2; h′ is selected from 0, 1, and 2; g isselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′ is selected from0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; s is selected from 0, 1, 2, 3, 4,5, 6, 7, 8, 9, and 10; s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,and 10; s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t isselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; x is selected from 0, 1, 2, 3, 4,and 5; x′ is selected from 0, 1, 2, 3, 4, and 5; C_(h) is a metalbonding unit having a formula selected from the group:

A¹, A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), O, OH, PR¹³,PR¹³R¹⁴, P(O)R¹⁵R¹⁶, and a bond to L_(n); E is a bond, CH, or a spacergroup independently selected at each occurrence from the group: C₁-C₁₀alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷, C₃-10cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkyl substitutedwith 0-3 R¹⁷, wherein the heterocyclo group is a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkyl substituted with 0-3R¹⁷, C₁₋₁₀alkyl-C₆₋₁₀ aryl-substituted with 0-3 R¹⁷, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹⁷; R¹³ and R¹⁴ areeach independently selected from the group: a bond to L_(n), hydrogen,C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷,C₁₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkylsubstituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkylsubstituted with 0-3 R¹⁷, C₁₋₁₀alkyl-C₆₋₁₀ aryl-substituted with 0-3R¹⁷, a 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R¹⁷,and an electron, provided that when one of R¹³ or R¹⁴ is an electron,then the other is also an electron; alternatively, R¹³ and R¹⁴ combineto form ═C(R²⁰)(R²¹); R¹⁵ and R¹⁶ are each independently selected fromthe group: a bond to L_(n), —OH, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷,C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, aryl substituted with 0-3 R¹⁷,C₃₋₁₀ cycloalkyl substituted with 0-3 R¹⁷, heterocyclo-C₁₋₁₀ alkylsubstituted with 0-3 R¹⁷, wherein the heterocyclo group is a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O, C₆₋₁₀ aryl-C₁₋₁₀ alkylsubstituted with 0-3 R¹⁷, C₁₋₁₀ alkyl-C₆₋₁₀ aryl-substituted with 0-3R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R¹⁷; R¹⁷ is independently selected at each occurrence from thegroup: a bond to L_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸,—C(═O)N(R¹⁸)₂, —CHO, —CH₂OR¹⁸, —OC(═O)R¹⁸, OC(═O)OR^(18a), —OR¹⁸,—OC(═O)N(R¹⁸)₂, —NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂,—NR¹⁹SO₂N(R¹⁸)₂, —NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —SR¹⁸,—S(═O)R^(18a), —SO₂N(R¹⁸)₂, —N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, NO₂,—C(═O)NHOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, 2-(1-morpholino)ethoxy,C₁-C₅ alkyl, C₂-C₄ alkenyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylmethyl,C₂-C₆ alkoxyalkyl, aryl substituted with 0-2 R¹⁸, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O; R¹⁸, R^(18a), and R¹⁹ are independentlyselected at each occurrence from the group: a bond to L_(n), H, C₁-C₆alkyl, phenyl, benzyl, C₁-C₆ alkoxy, halide, nitro, cyano, andtrifluoromethyl; Pg is a thiol protecting group; R²⁰ and R²¹ areindependently selected from the group: H, C₁-C₁₀ alkyl, —CN, —CO₂R²⁵,—C(═O)R²⁵, —C(═O)N(R²⁵)₂, C₂-C₁₀ 1-alkene substituted with 0-3 R²³,C₂-C₁₀ 1-alkyne substituted with 0-3 R²³, aryl substituted with 0-3 R²³,unsaturated 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R²³, and unsaturated C₃₋₁₀ carbocycle substituted with 0-3 R²³;alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

R²² and R²³ are independently selected from the group: H, R²⁴, C₁-C₁₀alkyl substituted with 0-3 R²⁴, C₂-C₁₀ alkenyl substituted with 0-3 R²⁴,C₂-C₁₀ alkynyl substituted with 0-3 R²⁴, aryl substituted with 0-3 R²⁴,a 5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²⁴,and C₃₋₁₀ carbocycle substituted with 0-3 R²⁴; alternatively, R²², R²³taken together form a fused aromatic or a 5-10 membered heterocyclicring system containing 1-4 heteroatoms independently selected from N, S,and O; a and b indicate the positions of optional double bonds and n is0 or 1; R²⁴ is independently selected at each occurrence from the group:═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R²⁵, —C(═O)R²⁵, —C(═O)N(R²⁵)₂,—N(R²⁵)₃+, —CH₂OR²⁵, —OC(═O)R²⁵, —OC(═O)OR^(25a), —OR²⁵, —OC(═O)N(R²⁵)₂,—NR²⁶C(═O)R²⁵—NR²⁶C(═O)OR^(25a), —NR²⁶C(═O)N(R²⁵)₂,—NR²⁶SO₂N(R²⁵)₂—NR²⁶SO₂R^(25a), —SO₃H, —SO₂R^(25a), —SR²⁵,—S(═O)R^(25a), —SO₂N(R²⁵)₂, —N(R²⁵)₂, ═NOR²⁵, —C(═O)NHOR²⁵, —OCH₂CO₂H,and 2-(1-morpholino)ethoxy; and, R²⁵, R^(25a), and R²⁶ are eachindependently selected at each occurrence from the group: hydrogen andC₁-C₆ alkyl; and a pharmaceutically acceptable salt thereof.
 3. Acompound according to claim 2, wherein Q is a compound of Formula (IV):

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein: R^(1e) is selected from:

R^(2e) and R^(3e) are independently selected from: H, C₁-C₄ alkoxy,NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and arylsubstituted with 0-4 R^(7e), alternatively, when R^(2e) and R^(3e) aresubstituents on adjacent atoms, they can be taken together with thecarbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being substituted with 0-2groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃and NO₂; R^(2ae) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl,C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl,aryloxycarbonyl, aryl (C₁-C₁₀ alkoxy) carbonyl, C₁-C₆alkylcarbonyloxy(C-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl; R^(7e)is selected from: H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl,aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl) carbonyl, CO₂R^(18ae), SO₂R^(11e),SO₂NR^(11e)R^(11e), OR^(10e), and N(R^(11e))R^(12e), U^(e) is selectedfrom: —(CH₂)_(n) ^(e)—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —NH (CH₂)_(n)^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)_(n) ^(e)—, and—C(═O)N(R^(10e))—; G^(e) is N or CR^(19e); R^(8e) is selected from: H,CO₂R^(18be), C(═O)R^(18be), CONR^(17e)R^(18be), C₁-C₁₀ alkyl substitutedwith 0-1 R^(6e), C₂-C₁₀ alkenyl substituted with 0-1 R^(6e), C₂-C₁₀alkynyl substituted with 0-1 R^(6e), C₃-C₈ cycloalkyl substituted with0-1 R^(6e), C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e), (C₁-C₁₀alkyl) carbonyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, phenyl substitutedwith 0-3 R^(6e), naphthyl substituted with 0-3 R^(6e), a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 R^(7e);R^(9e) is selected from: C₁-C₁₀ alkyl substituted with 0-1 R^(6e),C₁-C₁₀ alkoxy substituted with 0-2 R^(7e), H, nitro, N(R^(11e))R^(12e),OC(═O) R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O) R^(10e),NR^(10e)C(═O) OR^(21e), NR^(10e)C(═O)NR^(10e)R^(11e),NR^(10e)SO₂NR^(10e)R^(11e), NR^(10e)SO₂R^(21e), hydroxy, OR^(22e),—N(R^(10e))R^(11e), —N(R^(16e))R^(17e), aryl(C₀-C₆ alkyl)carbonyl,aryl(C₁-C₆ alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18ae)R^(20e),SO₂R^(18ae), and SO₂NR^(18ae)R^(20e), providing that any of the abovealkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted orsubstituted independently with 1-2 R^(7e); R^(6e) is selected from: H,C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be), C(═O)R^(18be),CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e),NR^(10e)C(═O) R^(10e), NR^(10e)C(═O) OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p) ^(e)R^(11e), SO₂NR^(10e)R^(11e), arylsubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂, aryl(C₁-C₄ alkyl)-, said arylbeing substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me, and —NMe₂, and a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 R^(7e);R^(10e) is selected from: H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R^(6e); R^(11e) is selected from: H, hydroxy, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl,C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀ alkyl substituted with0-2 R^(4e); R^(4e) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-,and heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,R^(12e) is selected from: H, C₁-C₆ alkyl, triphenylmethyl,methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl,(C₁-C₆ alkyl) carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl,heteroarylcarbonyl, aryl (C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl,arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl, wherein said arylgroups are substituted with 0-2 substituents selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R^(16e)is selected from: —C(═O)OR^(18ae), —C(═O)R^(18be), —C(═O)N(R^(18be))2—SO₂R^(18ae), and —SO₂N(R^(18be))₂; R^(17e) is selected from: H, C₁-C₆alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl); R^(18ae) is selectedfrom: C₁-C₈ alkyl optionally substituted with a bond to L_(n), C₃-C₁₁cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e); R^(18be)is H or R^(18ae); R^(19e) is selected from: H, halogen, CF₃, CO₂H, CN,NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-,C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—,heteroaryl, and heteroaryl-SO₂—, wherein said aryl and heteroaryl groupsare substituted with 0-4 groups selected from hydrogen, halogen, CF₃,C₁-C₃ alkyl, and C₁-C₃ alkoxy; R^(20e) is selected from: hydroxy, C₁-C₁₀alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)-; R^(21e) is selected from: C₁-C₈alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl,aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R^(7e);R^(22e) is selected from: —C(═O)—R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), —C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and—C(═O)NHSO₂NHR^(18be); m^(e) is 0-2; n^(e) is 0-4; and p^(e) is 0-2;with the following proviso: n^(e) and m^(e) are chosen such that thenumber of atoms connecting R¹ and —COR^(20e) in Formula (IV) is in therange of 8-14; d is selected from 1, 2, 3, 4, and 5; d′ is 1-50; W isindependently selected at each occurrence from the group: O, NH,NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O, OC(═O), NHC(═S)NH,NHC(═O)NH, SO₂, (OCH₂CH₂)_(s), (CH₂CH₂O)_(s′), (OCH₂CH₂CH₂)_(s″),(CH₂CH₂CH₂O)_(t), and (aa)_(t′); aa is independently at each occurrencean amino acid; Z is selected from the group: aryl substituted with 0-1R¹⁰, C₃₋₁₀ cycloalkyl substituted with 0-1 R¹⁰, and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-1 R¹⁰; R⁶, R^(6a), R⁷,R^(7a), and R⁸ are independently selected at each occurrence from thegroup: H, ═O, COOH, SO₃H, C₁-C₅ alkyl substituted with 0-1 R¹⁰, arylsubstituted with 0-1 R¹⁰, benzyl substituted with 0-1 R¹⁰, and C₁-C₅alkoxy substituted with 0-1 R¹⁰, NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹,NHR¹¹, R¹¹, and a bond to C_(h); k is 0 or 1; s is selected from 0, 1,2, 3, 4, and 5; s′ is selected from 0, 1, 2, 3, 4, and 5; s″ is selectedfrom 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; A¹,A², A³, A⁴, A⁵, A⁶, A⁷, and A⁸ are independently selected at eachoccurrence from the group: NR¹³, NR¹³R¹⁴, S, SH, S(Pg), OH, and a bondto L_(n); E is a bond, CH, or a spacer group independently selected ateach occurrence from the group: C₁-C₁₀ alkyl substituted with 0-3 R¹⁷,aryl substituted with 0-3 R¹⁷, C₃₋₁₀ cycloalkyl substituted with 0-3R¹⁷, and a 5-10 membered heterocyclic ring system containing 1-4heteroatoms independently selected from N, S, and O and substituted with0-3 R¹⁷; R¹³, and R¹⁴ are each independently selected from the group: abond to L_(n), hydrogen, C₁-C₁₀ alkyl substituted with 0-3 R¹⁷, arylsubstituted with 0-3 R¹⁷, a 5-10 membered heterocyclic ring systemcontaining 1-4 heteroatoms independently selected from N, S, and O andsubstituted with 0-3 R¹⁷, and an electron, provided that when one of R¹³or R¹⁴ is an electron, then the other is also an electron;alternatively, R¹³ and R¹⁴ combine to form ═C(R²⁰)(R²¹); R¹⁷ isindependently selected at each occurrence from the group: a bond toL_(n), ═O, F, Cl, Br, I, —CF₃, —CN, —CO₂R¹⁸, —C(═O)R¹⁸, —C(═O)N(R¹⁸)₂,—CH₂OR¹⁸, —OC(═O)R¹⁸, OC(═O)OR^(18a), —OR¹⁸, —OC(═O)N(R¹⁸)₂,—NR¹⁹C(═O)R¹⁸, —NR¹⁹C(═O)OR^(18a), —NR¹⁹C(═O)N(R¹⁸)₂, —NR¹⁹SO₂N(R¹⁸)₂,—NR¹⁹SO₂R^(18a), —SO₃H, —SO₂R^(18a), —S(═O)R^(18a), —SO₂N(R¹⁸)₂,—N(R¹⁸)₂, —NHC(═S)NHR¹⁸, ═NOR¹⁸, —C(═O)NHNR¹⁸R^(18a), —OCH₂CO₂H, and2-(1-morpholino)ethoxy; R¹⁸, R^(18a), and R¹⁹ are independently selectedat each occurrence from the group: a bond to L_(n), H, and C₁-C₆ alkyl;R²⁰ and R²¹ are independently selected from the group: H, C₁-C₅ alkyl,—CO₂R²⁵, C₂-C₅ 1-alkene substituted with 0-3 R²³, C₂-C₅ 1-alkynesubstituted with 0-3 R²³, aryl substituted with 0-3 R²³, and unsaturated5-10 membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O and substituted with 0-3 R²³;alternatively, R²⁰ and R²¹, taken together with the divalent carbonradical to which they are attached form:

R²² and R²³ are independently selected from the group: H, and R²⁴;alternatively, R²², R²³ taken together form a fused aromatic or a 5-10membered heterocyclic ring system containing 1-4 heteroatomsindependently selected from N, S, and O; R²⁴ is independently selectedat each occurrence from the group: —CO₂R²⁵, —C(═O)N(R²⁵)₂, —CH₂OR²⁵,—OC(═O)R²⁵, —OR²⁵, —SO₃H, —N(R²⁵)₂, and —OCH₂CO₂H; and, R²⁵ isindependently selected at each occurrence from the group: H and C₁-C₃alkyl.
 4. A compound according to claim 3, including stereoisomericforms thereof, or mixtures of stereoisomeric forms thereof, orpharmaceutically acceptable salt or prodrug forms thereof wherein:R^(1e) is selected from:

R^(2e) and R^(3e) are independently selected from: H, C₁-C₄ alkoxy,NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and arylsubstituted with 0-4 R^(7e), alternatively, when R^(2e) and R^(3e) aresubstituents on adjacent atoms, they can be taken together with thecarbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being substituted with 0-2groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃and NO₂; R^(2ae) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl,C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl,aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;R^(7e) is selected from: H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl,aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e),SO₂NR^(10e)R^(11e), OR^(10e), and N(R^(11e))R^(12e); U^(e) is selectedfrom: —(CH₂)_(n) ^(e)—, —NH(CH₂)_(n) ^(e)—, —N(R^(10e))C(═O)—, and—NHC(═O)(CH₂)_(n) ^(e); G^(e) is N or CR^(19e); R^(8e) is H; R^(9e) isselected from: H, nitro, N(R^(11e))R^(12e), OC(═O)R^(10e), OR^(10e),OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(11e)R^(11e)NR^(10e)SO₂R^(21e), hydroxy, OR^(22e), —N(R^(10e))R^(11e),N(R^(16e))R^(17e), aryl (C₀-C₄ alkyl) carbonyl, aryl (C₁-C₄ alkyl),heteroaryl(C₁-C₄ alkyl), CONR^(18ae)R^(20e), SO₂R^(18ae), andSO₂NR^(18ae)R^(20e), providing that any of the above alkyl, cycloalkyl,aryl or heteroaryl groups may be unsubstituted or substitutedindependently with 1-2 R^(7e); R^(10e) is selected from: H, CF₃, C₃-C₆alkenyl, C₃-C₆ cycloalkyl, aryl, (C₃-C₆ cycloalkyl)methyl, aryl(C₁-C₄alkyl), and C₁-C₄ alkyl substituted with 0-2 R^(6e); R^(6e) is selectedfrom: H, C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy, nitro, C₁-C₄ alkylcarbonyl,—N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be), C(═O)R^(18be),CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e),NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O) R^(11e), SO₂NR^(10e)R^(11e), aryl substitutedwith 0-3 groups selected from halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, CF₃,S(O)_(m) ^(e)Me, and —NMe₂, aryl(C₁-C₄ alkyl)-, said aryl beingsubstituted with 0-3 groups selected from halogen, C₁-C₄ alkoxy, C₁-C₄alkyl, CF₃, S(O)_(p) ^(e)Me, and —NMe₂, and a 5-10 membered heterocyclicring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclicring may be saturated, partially saturated, or fully unsaturated, saidheterocyclic ring being substituted with 0-2 R^(7e); R^(11e) is selectedfrom: H, hydroxy, C₁-C₄ alkyl, C₃-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆cycloalkyl)methyl, C₁-C₄ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₄alkyl substituted with 0-2 R^(4e); R^(4e) is selected from: H, C₁-C₄alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl, aryl(C₁-C₄ alkyl)-, and heteroaryl(C₁-C₄ alkyl)-, whereinsaid aryl or heteroaryl groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂, R^(12e) is selected from: H, C₁-C₄alkyl, (C₁-C₄ alkyl)carbonyl, (C₁-C₄ alkoxy) carbonyl, phenyl (C₁-C₄alkyl)-, phenylsulfonyl, phenyloxycarbonyl, and phenyl(C₁-C₄alkoxy)carbonyl, wherein said phenyl groups are substituted with 0-2substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and nitro; R^(16e) is selected from: —C(═O)OR^(18ae),—C(═O)R^(18be), —C(═O)N(R^(18be)) 2, —SO₂R^(18ae), and —SO₂N(R^(18be))₂;R^(17e) is selected from: H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl(C₁-C₄ alkyl)-, aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆alkyl); R^(18ae) is selected from: C₁-C₈ alkyl optionally substitutedwith a bond to L_(n), C₃-C₁₁ cycloalkyl optionally substituted with abond to L_(n), aryl(C₁-C₆ alkyl)- optionally substituted with a bond toL_(n), heteroaryl(C₁-C₆ alkyl)- optionally substituted with a bond toL_(n), (C₁-C₆ alkyl)heteroaryl optionally substituted with a bond toL_(n), biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e); R^(18be)is H or R^(18ae); R^(19e) is selected from: H, halogen, CF₃, CO₂H, CN,NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₄ alkyl)-,C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—,heteroaryl, and heteroaryl-SO₂—, wherein said aryl and heteroaryl groupsare substituted with 0-4 groups selected from hydrogen, halogen, CF₃,C₁-C₃ alkyl, and C₁-C₃ alkoxy; R^(20e) is selected from: hydroxy, C₁-C₆alkyloxy, C₃-C₆ cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)-; R^(21e) is selected from: C₁-C₄alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)methyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R^(7e);R^(22e) is selected from: —C(═O)—R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), —C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and—C(═O)NHSO₂NHR^(18be); m^(e) is 0-2; n^(e) is 0-4; p^(e) is 0-2; C_(h)is

A¹ is selected from the group: OH, and a bond to L_(n); A², A⁴, and A⁶are each N; A³, A⁵, and A⁸ are each OH; A⁷ is a bond to L_(n) or NH-bondto L_(n); E is a C₂ alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O;alternatively, C_(h) is

A¹ is selected from the group: OH, and a bond to L_(n); A², A³ and A⁴are each N; A⁵, A⁶ and A⁸ are each OH; A⁷ is a bond to L_(n); E is a C₂alkyl substituted with 0-1 R¹⁷; R¹⁷ is ═O; alternatively, C_(h) is

A¹ is NH₂ or N═C(R²⁰)(R²¹); E is a bond; A² is NHR¹³; R¹³ is aheterocycle substituted with R¹⁷, the heterocycle being selected frompyridine and pyrimidine; R¹⁷ is selected from a bond to L_(n),C(═O)NHR¹⁸ and C(═O)R¹⁸; R¹⁸ is a bond to L_(n); R²⁴ is selected fromthe group: —CO₂R²⁵, —OR²⁵, —SO₃H, and —N(R²⁵)₂; and, R²⁵ isindependently selected at each occurrence from the group: hydrogen andmethyl.
 5. A compound according to claim 2, including enantiomeric ordiastereomeric forms thereof, or mixtures of enantiomeric ordiastereomeric forms thereof, or pharmaceutically acceptable salt orprodrug forms thereof, wherein Q is selected from the group:3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylainino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]—1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionicacid,3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphen-yl)sulfonylamino)propionicacid,3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]pro-pionicacid,3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionicacid,3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfon-ylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6-dichlorophenyl)sulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionicacid,3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid,3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid, and3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionicacid.
 6. A compound according to claim 2, wherein the compound isselected from the group:2-(((4-(4-(((3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid;3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)propanoicacid;2-(((4-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic;3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid;3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid;3-((1-(3-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid;2-(2-aza-2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonicacid;

2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid conjugate; and2-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid;

or a pharmaceutically acceptable salt form thereof.
 7. A kit comprisinga compound of claim 2, or a pharmaceutically acceptable salt formthereof and a pharmaceutically acceptable carrier.
 8. A kit according toclaim 7, wherein the kit further comprises one or more ancillary ligandsand a reducing agent.
 9. A kit according to claim 8, wherein theancillary ligands are tricine and TPPTS.
 10. A kit according to claim 8,wherein the reducing agent is tin(II).
 11. A diagnostic or therapeuticmetallopharmaceutical composition, comprising: a metal, a chelatorcapable of chelating the metal and a targeting moiety, wherein thetargeting moiety is bound to the chelator, is a quinolone non-peptideand binds to a receptor that is upregulated during angiogenesis and thecompound has 0-1 linking groups between the targeting moiety andchelator.
 12. A composition according to claim 11, wherein themetallopharmaceutical is a diagnostic radiopharmaceutical, the metal isa radioisotope selected from the group: ^(99m)TC, ⁹⁵Tc, ¹¹¹In, ⁶²Cu,⁶⁴Cu, ⁶⁷Ga, and ⁶⁸Ga, and the linking group is present between thenon-peptide targeting moiety and chelator.
 13. A composition accordingto claim 12, wherein the targeting moiety is a quinolone non-peptide andthe receptor is α_(v)β₃ or α_(v)β₅.
 14. A composition according to claim13, wherein the radioisotope is ^(99m)Tc or ⁹⁵Tc, theradiopharmaceutical further comprises a first ancillary ligand and asecond ancillary ligand capable of stabilizing the radiopharmaceutical.15. A composition according to claim 14, wherein the radioisotope is^(99m)Tc.
 16. A composition according to claim 15, wherein theradiopharmaceutical is selected from the group: ^(99m)Tc(2-(((4-(4-(((3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid)(tricine)(TPPTS); ^(99m)Tc(2-(((4-(3-(N-(3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoicacid)(tricine)(TPPDS);^(99m)Tc(3-((1-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid)(tricine)(TPPTS);^(99m)Tc(3-((1-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid)(tricine)(TPPTS);^(99m)Tc(3-((1-(3-(3-(N-(3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoicacid)(tricine)(TPPTS); ^(99m)Tc (2-(2-(5-(N-(1, 3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl)diazenido))(tricine)(TPPTS);^(99m)Tc(3-{[1-(3-{2-[(6-(diazenido)(3-pyridyl))carbonylamino](2R)-3-sulfopropyl}propyl)-7-[(imidazol-2-ylamino)methyl]-4-oxo(3-hydroquinolyl)]carbonylamino}(2S)-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}propanoicacid) (tricine)(TPPTS).
 17. A composition according to claim 13, whereinthe radioisotope is ¹¹In.
 18. A composition according to claim 17,wherein the radiopharmaceutical is selected from the group:


19. A composition according to claim 11, wherein themetallopharmaceutical is a therapeutic radiopharmaceutical, the metal isa radioisotope selected from the group: ¹⁸⁶Re, ¹⁸⁸Re, ¹⁵³Sm, ¹⁶⁶Ho,¹⁷⁷Lu, ¹⁴⁹Pm, ⁹⁰Y, ²¹²Bi, ¹⁰³Pd, ¹⁰⁹Pd, ¹⁵⁹Gd, ¹⁴⁰La, ¹⁹⁸Au, ¹⁹⁹Au,¹⁶⁹Yb, ¹⁷⁵Yb, ¹⁶⁵Dy, ¹⁶⁶Dy, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, and ¹⁹²Ir, and thelinking group is present between the non-peptide targeting moiety andchelator.
 20. A composition according to claim 19, wherein the targetingmoiety is a quinolone non-peptide and the receptor is α_(v)β₃ orα_(v)β₅.
 21. A composition according to claim 20, wherein theradioisotope is ¹⁵³Sm.
 22. A composition according to claim 20, whereinthe radioisotope is ¹⁷⁷Lu.
 23. A composition according to claim 22,wherein the radiopharmaceutical is selected from the group:


24. A composition according to claim 20, wherein the radioisotope is⁹⁰Y.
 25. A composition according to claim 24, wherein theradiopharmaceutical is selected from the group;


26. A composition according to claim 11, wherein themetallopharmaceutical is a MRI contrast agent, the metal is aparamagnetic metal ion selected from the group: Gd(III), Dy(III),Fe(III), and Mn(II), the targeting moiety is a quinolone nonpeptide andthe linking group is present between the targeting moiety and chelator.27. A composition according to claim 26, wherein the targeting moiety isquinolone non-peptide and the receptor is α_(v)β₃ or α_(v)β₅.
 28. Acomposition according to claim 27, wherein the metal ion is Gd(III). 29.A composition according to claim 28, wherein the contrast agent is


30. A composition according to claim 11, wherein themetallopharmaceutical is a X-ray contrast agent, the metal is selectedfrom the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy,Cu, Rh, Ag, and Ir, the targeting moiety is a quinolone non-peptide, thereceptor is α_(v)β₃ or α_(v)β₅, and the linking group is present betweenthe targeting moiety and chelator.
 31. A method of treating rheumatoidarthritis in a patient comprising: administering a therapeuticradiopharmaceutical of claim 19 capable of localizing in new angiogenicvasculature to a patient by injection or infusion.
 32. A method oftreating cancer in a patient comprising: administering to a patient inneed thereof a therapeutic radiopharmaceutical of claim 19 by injectionor infusion.
 33. A method of imaging therapeutic angiogenesis in apatient comprising: (1) administering a diagnostic radiopharmaceutical,a MRI contrast agent, or a X-ray contrast agent of claim 11 to a patientby injection or infusion; (2) imaging the area of the patient whereinthe desired formation of new blood vessels is located.
 34. A method ofimaging cancer in a patient comprising: (1) administering a diagnosticradiopharmaceutical of claim 12 to a patient by injection or infusion;(2) imaging the patient using planar or SPECT gamma scintigraphy, orpositron emission tomography.
 35. A method of imaging cancer in apatient comprising: (1) administering a MRI contrast agent of claim 26;and (2) imaging the patient using magnetic resonance imaging.
 36. Amethod of imaging cancer in a patient comprising: (1) administering aX-ray contrast agent of claim 30; and (2) imaging the patient usingX-ray computed tomography.
 37. A compound, comprising: a targetingmoiety and a surfactant, wherein the targeting moiety is bound to thesurfactant, is a nonpeptide, and binds to a receptor that is upregulatedduring angiogenesis and the compound has 0-1 linking groups between thetargeting moiety and surfactant.
 38. A compound according to claim 37,wherein the targeting moiety comprises a quinolone non-peptide and thelinking group is present between the targeting moiety and surfactant.39. A compound according to claim 38, wherein the receptor is theintegrin α_(v)β₃ or α_(v)β₅ and the compound is of the formula:(Q)_(d)—L_(n)—S_(f) wherein, Q is a compound of Formula (II):

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein: R^(1e) is selected from:

A^(e) is —CH₂— or —N(R^(10e))—; A^(1e) and B^(e) are independently —CH₂—or —N(R^(10e))—; D^(e) is —N(R^(10e))— or —S—; E^(e)-F^(e) is—C(R^(2e))═C(R^(3e))— or —C(R^(2e))₂C(R^(3e))₂—; J^(e) is —C(R^(2e))— or—N—; K^(e), L^(e) and M^(e) are independently —C(R^(2e))— or—C(R^(3e))—; R^(2e) and R^(3e) are independently selected from: H, C₁-C₄alkoxy, NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl,and aryl substituted with 0-4 R^(7e), alternatively, when R^(2e) andR^(3e) are substituents on adjacent atoms, they can be taken togetherwith the carbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being substituted with 0-2groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃and NO₂; R^(2ae) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl,C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl,aryloxycarbonyl, aryl (C₁-C₁₀ alkoxy) carbonyl, C₁-C₆alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;R^(7e) is selected from: H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl,aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e),SO₂NR^(10e)R^(11e), OR^(10e), and N(R^(11e))R^(12e); U^(e) is selectedfrom: —(CH₂)_(n) ^(e)—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —(CH₂)_(n)^(e)N(R¹²)(CH₂)_(m) ^(e)—, —NH(CH₂)_(n) ^(e)—, —(CH₂)_(n)^(e)C(═O)(CH₂)_(m) ^(e)—, (CH₂)_(n) ^(e)S(O)_(p) ^(e)(CH₂)_(m) ^(e)—,—(CH₂)_(n) ^(e)NHNH(CH₂)_(m) ^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)e—,—C(═O)N(R^(10e))—, and —N(R^(10e))S(O)_(p) ^(e)—; G^(e) is N orCR^(19e); W^(e) is —C(═O)—N(R^(10e))—(C₁-C₃ alkylene)-, in which thealkylene group is substituted by R^(8e) and by R^(9e): R^(8e) and R^(9e)are independently selected from: H, CO₂R^(18be), C(═O)R^(18be),CONR¹⁷R^(18be), C₁-C₁₀ alkyl substituted with 0-1 R^(6e), C₂-C₁₀ alkenylsubstituted with 0-1 R^(6e), C₂-C₁₀ alkynyl substituted with 0-1 R^(6e),C₃-C₈ cycloalkyl substituted with 0-1 R^(6e), C₅-C₆ cycloalkenylsubstituted with 0-1 R^(6e), (C₁-C₁₀ alkyl) carbonyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, phenyl substituted with 0-3 R^(6e), naphthylsubstituted with 0-3 R^(6e), a 5-10 membered heterocyclic ringcontaining 1-3 N, O, or S heteroatoms, wherein said heterocyclic ringmay be saturated, partially saturated, or fully unsaturated, saidheterocyclic ring being substituted with 0-2 R^(7e), C₁-C₁₀ alkoxysubstituted with 0-2 R^(7e), hydroxy, nitro, —N(R^(10e))R^(11e),—N(R^(16e))R^(17e), aryl(C₀-C₆ alkyl)carbonyl, aryl(C₃-C₆ alkyl),heteroaryl (C₁-C₆ alkyl), CONR^(18ae)R^(20e), SO₂R^(18ae), andSO₂NR^(18ae)R^(20e), providing that any of the above alkyl, cycloalkyl,aryl or heteroaryl groups may be unsubstituted or substitutedindependently with 1-2 R^(7e); R^(6e) is selected from: H, C₁-C₁₀ alkyl,hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl, —N(R^(11e))R^(12e),cyano, halo, CF₃, CHO, CO₂R^(18be), C(═O)R^(18be), CONR^(17e)R^(18be),OC(═O)R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O) R^(10e),NR^(11e)C(═O) OR^(21e), NR^(10e)C(═O)NR^(10e)R^(11e),NR^(10e)SO₂NR^(10e)R^(11e), NR^(10e)SO₂R^(21e), S(O)_(p)R^(11e),SO₂NR^(10e)R^(11e), aryl substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂,aryl(C₁-C₄ alkyl)-, said aryl being substituted with 0-3 groups selectedfrom halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me, and—NMe₂, and a 5-10 membered heterocyclic ring containing 1-3 N, O, or Sheteroatoms, wherein said heterocyclic ring may be saturated, partiallysaturated, or fully unsaturated, said heterocyclic ring beingsubstituted with 0-2 R^(7e); R^(10e) is selected from: H, CF₃, C₃-C₆alkenyl, C₃-C₁₁ cycloalkyl, aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄alkyl), and C₁-C₁₀ alkyl substituted with 0-2 R^(6e); R^(11e) isselected from: H, hydroxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl,(C₃-C₁₁ cycloalkyl)methyl, C₁-C₆ alkoxy, benzyloxy, aryl, heteroaryl,heteroaryl(C₁-C₄ alkyl), aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀alkyl substituted with 0-2 R^(4e); R^(4e) is selected from: H, C₁-C₆alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl (C₁-C₄ alkyl)-, (C₁-C₁₀alkyl)carbonyl, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-, andheteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,alternatively, when R^(10e) and R^(11e) are both substituents on thesame nitrogen atom (as in —NR^(10e)R^(11e)) they may be taken togetherwith the nitrogen atom to which they are attached to form a heterocycleselected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl,1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; saidheterocycle being substituted with 0-3 groups selected from: C₁-C₆alkyl, aryl, heteroaryl, aryl(C₁-C₄ alkyl)-, (C₁-C₆ alkyl)carbonyl,(C₃-C₇ cycloalkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, aryl(C₁-C₄alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, and arylsulfonyl; R^(12e) isselected from: H, C₁-C₆ alkyl, triphenylmethyl, methoxymethyl,methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆ alkyl)aminocarbonyl, C₃-C₆alkenyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,heteroaryl(C₁-C₆ alkyl)carbonyl, heteroarylcarbonyl, aryl (C₁-C₆alkyl)-, (C₁-C₆ alkyl)carbonyl, arylcarbonyl, C₁-C₆ alkylsulfonyl,arylsulfonyl, aryl(C₁-C₆ alkyl)sulfonyl, heteroarylsulfonyl,heteroaryl(C₁-C₆ alkyl)sulfonyl, aryloxycarbonyl, and aryl(C₁-C₆alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2substituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and nitro; R^(16e) is selected from: —C(═O)OR^(18ae),C(═O)R^(18be), —C(═O)N(R^(18be))₂, —C(═O)NHSO₂R^(18ae),—C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), —C(═O)NHSO₂NHR^(18be),—SO₂R^(18ae), —SO₂N(R^(18be))₂, and —SO₂NHC(═O)OR^(18be); R^(17e) isselected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄alkyl)-, aryl, aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl); R^(18ae)is selected from: C₁-C₈ alkyl optionally substituted with a bond toL_(n), C₃-C₁₁ cycloalkyl optionally substituted with a bond to L_(n),aryl(C₁-C₆ alkyl)- optionally substituted with a bond to L_(n),heteroaryl(C₁-C₆ alkyl)- optionally substituted with a bond to L_(n),(C₁-C₆ alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e); R^(18be)is H or R^(18ae); R^(19e) is selected from: H, halogen, CF₃, CO₂H, CN,NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-,C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—,heteroaryl, and heteroaryl-SO₂—, wherein said aryl and heteroaryl groupsare substituted with 0-4 groups selected from hydrogen, halogen, CF₃,C₁-C₃ alkyl, and C₁-C₃ alkoxy; R^(20e) is selected from: hydroxy, C₁-C₁₀alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-,aryloxycarbonyloxy(C₁-C₂ alkyl)oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-,C₁-C₅ alkoxy(C₁-C₅ alkyl)carbonyloxy(C₁-C₂ alkyl)oxy, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy) R^(21e) is selected from: C₁-C₈alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R^(7e);R^(22e) is selected from: —C(═O)—R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and—C(═O)NHSO₂NHR^(18be); Y^(e) is selected from: —COR^(20e), —SO₃H, —PO₃H,—CONHNHSO₂CF₃, —CONHSO₂R^(18ae), —CONHSO₂NHR^(18be), —NHCOCF₃,—NHCONHSO₂R^(18ae), —NHSO₂R^(18ae), —OPO₃H₂, —OSO₃H, —PO₃H₂,—SO₂NHCOR^(18ae), —SO₂NHCO₂R^(18ae),

m^(e) is 0-2; n^(e) is 0-4; p^(e) is 0-2; r^(e) is 0-2; with thefollowing proviso: n^(e) and m^(e) are chosen such that the number ofatoms connecting R^(1e) and Y^(e) is in the range of 8-14; d is selectedfrom 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; L_(n) is a linking group havingthe formula: ((W)_(h)—(CR⁶R⁷)_(g))_(x)—(Z)_(k)—(CR^(6a)R^(7a))_(g′),—(W)_(h′))_(x′); W is independently selected at each occurrence from thegroup: O, S, NH, NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O,OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)₂₀₋₂₀₀,(CH₂CH₂O)₂₀₋₂₀₀, (OCH₂CH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′);aa is independently at each occurrence an amino acid; Z is selected fromthe group: aryl substituted with 0-3 R¹⁰, C₃₋₁₀ cycloalkyl substitutedwith 0-3 R¹⁰, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-3 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), and R⁸ are independently selectedat each occurrence from the group: H, ═O, COOH, SO₃H, PO₃H, C₁-C₅ alkylsubstituted with 0-3 R¹⁰, aryl substituted with 0-3 R¹⁰, benzylsubstituted with 0-3 R¹⁰, and C₁-C₅ alkoxy substituted with 0-3 R¹⁰,NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to S_(f);R¹⁰ is independently selected at each occurrence from the group: a bondto S_(f), COOR¹¹, C(═O)NHR¹¹, NHC(═O)R ¹, OH, NHR¹¹, SO₃H, PO₃H,—OPO₃H₂, —OSO₃H, aryl substituted with 0-3 R¹¹, C₁₋₅ alkyl substitutedwith 0-1 R¹², C₁₋₅ alkoxy substituted with 0-1 R¹², and a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-3 R¹¹; R¹¹ isindependently selected at each occurrence from the group: H, alkylsubstituted with 0-1 R¹² aryl substituted with 0-1 R¹², a 5-10 memberedheterocyclic ring system containing 1-4 heteroatoms independentlyselected from N, S, and O and substituted with 0-1 R¹², C₃₋₁₀ cycloalkylsubstituted with 0-1 R¹², polyalkylene glycol substituted with 0-1 R¹²,carbohydrate substituted with 0-1 R¹², cyclodextrin substituted with 0-1R¹², amino acid substituted with 0-1 R¹², polycarboxyalkyl substitutedwith 0-1 R¹², polyazaalkyl substituted with 0-1 R¹², peptide substitutedwith 0-1 R¹², wherein the peptide is comprised of 2-10 amino acids,3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and abond to S_(f); R¹² is a bond to S_(f); k is selected from 0, 1, and 2; his selected from 0, 1, and 2; h′ is selected from 0, 1, and 2; g isselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g′ is selected from0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; t′ is selected from 0, 1, 2, 3, 4,5, 6, 7, 8, 9, and 10; x is selected from 0, 1, 2, 3, 4, and 5; x′ isselected from 0, 1, 2, 3, 4, and 5; S_(f) is a surfactant which is alipid or a compound of the formula:

A⁹ is selected from the group: OH and OR²⁷; A¹⁰ is OR²⁷; R²⁷ isC(═O)C₁₋₂₀ alkyl; E¹ is C₁₋₁₀ alkylene substituted with 1-3 R²⁸; R²⁸ isindependently selected at each occurrence from the group: R³⁰,—PO₃H-R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹, —C(═O)N(R²⁹)₂, —CH₂OR²⁹, —OR²⁹,—N(R²⁹)₂, C₁-C₅ alkyl, and C₂-C₄ alkenyl; R²⁹ is independently selectedat each occurrence from the group: R³⁰, H, C₁-C₆ alkyl, phenyl, benzyl,and trifluoromethyl; R³⁰ is a bond to L_(n); and a pharmaceuticallyacceptable salt thereof.
 40. A compound according to claim 39, whereinthe compound is of the formula: Q—L_(n)—S_(f) wherein, Q is a compoundof Formula (IV):

including stereoisomeric forms thereof, or mixtures of stereoisomericforms thereof, or pharmaceutically acceptable salt or prodrug formsthereof wherein: R^(1e) is selected from:

R^(2e) and R^(3e) are independently selected from: H, C₁-C₄ alkoxy,NR^(11e)R^(12e), halogen, NO₂, CN, CF₃, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl(C₁-C₆ alkyl)-,(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, arylcarbonyl, and arylsubstituted with 0-4 R^(7e), alternatively, when R^(2e) and R^(3e) aresubstituents on adjacent atoms, they can be taken together with thecarbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being substituted with 0-2groups selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano, amino, CF₃and NO₂; R^(2ae) is selected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl), aryl, aryl(C₁-C₄alkyl)-, (C₂-C₇ alkyl)carbonyl, arylcarbonyl, (C₂-C₁₀ alkoxy)carbonyl,C₃-C₇ cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl,aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy)carbonyl, C₁-C₆alkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and C₃-C₇ cycloalkylcarbonyloxy(C₁-C₄ alkoxy)carbonyl;R^(7e) is selected from: H, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, aryl,aryl(C₁-C₄ alkyl)-, (C₁-C₄ alkyl)carbonyl, CO₂R^(18ae), SO₂R^(11e),SO₂NR^(10e)R^(11e), OR^(10e), and N(R^(11e))R^(12e); U^(e) is selectedfrom: —(CH₂)_(n) ^(e)—, —(CH₂)_(n) ^(e)O(CH₂)_(m) ^(e)—, —NH(CH₂)_(n)^(e)—, —N(R^(10e))C(═O)—, —NHC(═O)(CH₂)_(n) ^(e)—, and—C(═O)N(R^(10e))—; G^(e) is N or CR^(19e); R^(8e) is selected from: H,CO₂R^(18be), C(═O)R^(18be), CONR^(17e)R^(18be), C₁-C₁₀ alkyl substitutedwith 0-1 R^(6e), C₂-C₁₀ alkenyl substituted with 0-1 R^(6e), C₂-C₁₀alkynyl substituted with 0-1 R^(6e), C₃-C₈ cycloalkyl substituted with0-1 R^(6e), C₅-C₆ cycloalkenyl substituted with 0-1 R^(6e), (C₁-C₁₀alkyl) carbonyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, phenyl substitutedwith 0-3 R^(6e), naphthyl substituted with 0-3 R^(6e), a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 R^(7e);R^(9e) is selected from: C₁-C₁₀ alkyl substituted with 0-1 R^(6e),C₁-C₁₀ alkoxy substituted with 0-2 R^(7e), H, nitro, N(R^(11e))R^(12e),OC(═O)R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e), NR^(10e)C(═O)R^(10e),NR^(10e)C(═O)OR^(21e), NR^(10e)C(═O)NR^(10e)R^(11e),NR^(10e)SO₂NR^(10e)R^(11e), NR^(10e)SO₂R^(21e), hydroxy, OR^(22e),—N(R^(10e))R^(11e), —N(R^(16e))R^(17e), aryl(C₀-C₆ alkyl)carbonyl,aryl(C₁-C₆ alkyl), heteroaryl(C₁-C₆ alkyl), CONR^(18ae)R^(20e),SO₂R^(18ae), and SO₂NR^(18ae)R^(20e), providing that any of the abovealkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted orsubstituted independently with 1-2 R^(7e); R^(6e) is selected from: H,C₁-C₁₀ alkyl, hydroxy, C₁-C₁₀ alkoxy, nitro, C₁-C₁₀ alkylcarbonyl,—N(R^(11e))R^(12e), cyano, halo, CF₃, CHO, CO₂R^(18be), C(═O)R^(18be),CONR^(17e)R^(18be), OC(═O)R^(10e), OR^(10e), OC(═O)NR^(10e)R^(11e),NR^(10e)C(═O)R^(10e), NR^(10e)C(═O)OR^(21e),NR^(10e)C(═O)NR^(10e)R^(11e), NR^(10e)SO₂NR^(10e)R^(11e),NR^(10e)SO₂R^(21e), S(O)_(p) ^(e)R^(11e), SO₂NR^(10e)R^(11e), arylsubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, S(O)_(m) ^(e)Me, and —NMe₂, aryl(C₁-C₄ alkyl)-, said arylbeing substituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy,C₁-C₆ alkyl, CF₃, S(O)_(p) ^(e)Me, and —NMe₂, and a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 R^(7e);R^(10e) is selected from: H, CF₃, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,aryl, (C₃-C₁₁ cycloalkyl)methyl, aryl(C₁-C₄ alkyl), and C₁-C₁₀ alkylsubstituted with 0-2 R^(6e); R^(11e) is selected from: H, hydroxy, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, (C₃-C₁₁ cycloalkyl)methyl, C₁-C₆alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-,aryl(C₁-C₄ alkyl), adamantylmethyl, and C₁-C₁₀ alkyl substituted with0-2 R^(4e); R^(4e) is selected from: H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl, aryl(C₁-C₆ alkyl)-,and heteroaryl(C₁-C₆ alkyl)-, wherein said aryl or heteroaryl groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂,R^(12e) is selected from: H, C₁-C₆ alkyl, triphenylmethyl,methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl,(C₁-C₆ alkyl)carbonyl, (C₁-C₆ alkoxy)carbonyl, (C₁-C₆alkyl)aminocarbonyl, C₃-C₆ alkenyl, C₃-C₇ cycloalkyl, C₃-C₇cycloalkyl(C₁-C₄ alkyl)-, aryl, heteroaryl(C₁-C₆ alkyl)carbonyl,heteroarylcarbonyl, aryl (C₁-C₆ alkyl)-, (C₁-C₆ alkyl)carbonyl,arylcarbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl, aryl(C₁-C₆alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C₁-C₆ alkyl)sulfonyl,aryloxycarbonyl, and aryl(C₁-C₆ alkoxy)carbonyl, wherein said arylgroups are substituted with 0-2 substituents selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, and nitro; R^(16e)is selected from: —C(═O)OR^(18ae), C(═O)R^(18be), —C(═O)N(R^(18be))₂,—SO₂R^(18ae), and —SO₂N(R^(18be))₂; R^(17e) is selected from: H, C₁-C₆alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, and heteroaryl(C₁-C₆ alkyl); R^(18ae) is selectedfrom: C₁-C₈ alkyl optionally substituted with a bond to L, C₃-C₁₁cycloalkyl optionally substituted with a bond to L_(n), aryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), heteroaryl(C₁-C₆alkyl)- optionally substituted with a bond to L_(n), (C₁-C₆alkyl)heteroaryl optionally substituted with a bond to L_(n),biaryl(C₁-C₆ alkyl) optionally substituted with a bond to L_(n),heteroaryl optionally substituted with a bond to L_(n), phenylsubstituted with 3-4 R^(19e) and optionally substituted with a bond toL_(n), naphthyl substituted with 0-4 R^(19e) and optionally substitutedwith a bond to L_(n), and a bond to L_(n), wherein said aryl orheteroaryl groups are optionally substituted with 0-4 R^(19e); R^(18be)is H or R^(18ae); R^(19e) is selected from: H, halogen, CF₃, CO₂H, CN,NO₂, —NR^(11e)R^(12e), OCF₃, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₁₁ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl)-, aryl(C₁-C₆ alkyl)-,C₁-C₆ alkoxy, C₁-C₄ alkoxycarbonyl, aryl, aryl-O—, aryl-SO₂—,heteroaryl, and heteroaryl-SO₂—, wherein said aryl and heteroaryl groupsare substituted with 0-4 groups selected from hydrogen, halogen, CF₃,C₁-C₃ alkyl, and C₁-C₃ alkoxy; R^(20e) is selected from: hydroxy, C₁-C₁₀alkyloxy, C₃-C₁₁ cycloalkyloxy, aryloxy, aryl(C₁-C₄ alkyl)oxy, C₂-C₁₀alkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₂-C₁₀ alkoxycarbonyloxy(C₁-C₂alkyl)oxy-, C₂-C₁₀ alkoxycarbonyl(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀cycloalkoxycarbonyloxy(C₁-C₂ alkyl)oxy-, C₃-C₁₀ cycloalkoxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyl(C₁-C₂ alkyl)oxy-, aryloxycarbonyloxy(C₁-C₂ alkyl) oxy-, arylcarbonyloxy(C₁-C₂ alkyl)oxy-, C₁-C₅ alkoxy(C₁-C₅alkyl)carbonyloxy(C₁-C₂ alkyl)oxy, (5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and(R^(10e))(R^(11e))N—(C₁-C₁₀ alkoxy)-; R^(21e) is selected from: C₁-C₈alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, (C₃-C₁₁cycloalkyl)methyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 0-2 R^(7e);R^(22e) is selected from: —C(═O)—R^(18be), —C(═O)N(R^(18be))₂,—C(═O)NHSO₂R^(18ae), C(═O)NHC(═O)R^(18be), —C(═O)NHC(═O)OR^(18ae), and—C(═O)NHSO₂NHR^(18be); m^(e) is 0-2; n^(e) is 0-4; and p^(e) is 0-2;with the following proviso: n^(e) and m^(e) are chosen such that thenumber of atoms connecting R¹ and —COR^(20e) in Formula (IV) is in therange of 8-14; W is independently selected at each occurrence from thegroup: O, S, NH, NHC(═O), C(═O)NH, NR⁸C(═O), C(═O)N R⁸, C(═O), C(═O)O,OC(═O), NHC(═S)NH, NHC(═O)NH, SO₂, SO₂NH, (OCH₂CH₂)₂₀₋₂₀₀,(CH₂CH₂O)₂₀₋₂₀₀, (OCH₂CH₂CH₂)₂₀₋₂₀₀, (CH₂CH₂CH₂O)₂₀₋₂₀₀, and (aa)_(t′),aa is independently at each occurrence an amino acid; Z is selected fromthe group: aryl substituted with 0-1 R¹⁰, C₃₋₁₀ cycloalkyl substitutedwith 0-1 R¹⁰, and a 5-10 membered heterocyclic ring system containing1-4 heteroatoms independently selected from N, S, and O and substitutedwith 0-1 R¹⁰; R⁶, R^(6a), R⁷, R^(7a), and R⁸ are independently selectedat each occurrence from the group: H, ═O, COOH, SO₃H, C₁-C₅ alkylsubstituted with 0-1 R¹⁰, aryl substituted with 0-1 R¹⁰, benzylsubstituted with 0-1 R¹⁰, and C₁-C₅ alkoxy substituted with 0-1 R¹⁰,NHC(═O)R¹¹, C(═O)NHR¹¹, NHC(═O)NHR¹¹, NHR¹¹, R¹¹, and a bond to S_(f); kis 0 or 1; S_(f) is a surfactant which is a lipid or a compound of theformula:

A⁹ is OR²⁷; A¹⁰ is OR²⁷; R²⁷ is C(═O)C₁₋₁₅ alkyl; E¹ is C₁₋₄ alkylenesubstituted with 1-3 R²⁸; R²⁸ is independently selected at eachoccurrence from the group: R³⁰, —PO₃H-R³⁰, ═O, —CO₂R²⁹, —C(═O)R²⁹,—CH₂OR²⁹, —OR²⁹, and C₁-C₅ alkyl; R²⁹ is independently selected at eachoccurrence from the group: R³⁰, H, C₁-C₆ alkyl, phenyl, and benzyl; R³⁰is a bond to L_(n); and a pharmaceutically acceptable salt thereof. 41.An ultrasound contrast agent composition, comprising: (a) a compound ofclaim 39, comprising: an quinolone that binds to the integrin α_(v)β₃ asurfactant and a linking group between the quinolone and the surfactant;(b) a parenterally acceptable carrier; and, (c) an echogenic gas.
 42. Anultrasound contrast agent composition of claim 41, further comprising:1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid,1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, andN-(methoxypolyethylene glycol 5000carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.
 43. Anultrasound contrast agent composition of claim 42, wherein the echogenicgas is a C₂₋₅ perfluorocarbon.
 44. A method of imaging cancer in apatient comprising: (1) administering, by injection or infusion, aultrasound contrast agent composition of claim 41 to a patient; and (2)imaging the patient using sonography.
 45. A method of imaging formationof new blood vessels in a patient comprising: (1) administering, byinjection or infusion, a ultrasound contrast agent composition of ofclaim 41 to a patient; (2) imaging the area of the patient wherein thedesired formation of new blood vessels is located.
 46. A method ofimaging therapeutic angiogenesis in a patient comprising: (1)administering, by injection or infusion, an ultrasound contrast agentcomposition of claim 41 to a patient; (2) imaging the area of thepatient wherein the desired formation of new blood vessels is located.47. A method of imaging atherosclerosis in a patient comprising: (1)administering, by injection or infusion, an ultrasound contrast agentcomposition of claim 41 to a patient; (2) imaging the area of thepatient wherein the atherosclerosis is located.
 48. A method of imagingrestenosis in a patient comprising: (1) administering, by injection orinfusion, an ultrasound contrast agent composition of claim 41 to apatient; (2) imaging the area of the patient wherein the restenosis islocated.
 49. A method of imaging cardiac ischemia in a patientcomprising: (1) administering, by injection or infusion, an ultrasoundcontrast agent composition of claim 41 to a patient; (2) imaging thearea of the myocardium wherein the ischemic region is located.
 50. Amethod of imaging myocardial reperfusion injury in a patient comprising:(1) administering, by injection or infusion, an ultrasound contrastagent composition of claim 41 to a patient; (2) imaging the area ofmyocardium wherein the reperfusion injury is located.
 51. A therapeuticradiopharmaceutical composition, comprising: (a) a therapeuticradiopharmaceutical of claim 19; and, (b) a parenterally acceptablecarrier.
 52. A diagnostic pharmaceutical composition, comprising: (a) adiagnostic radiopharmaceutical, a MRI contrast agent, or a X-raycontrast agent of claim 11; and, (b) a parenterally acceptable carrier.53. A method of treating restenosis in a patient comprising:administering to a patient, either systemically or locally, atherapeutic radiopharmaceutical of claim 19 capable of localizing in therestenotic area and delivering an effective dose of radiation.
 54. Amethod of imaging atherosclerosis in a patient comprising: (1)administering a diagnostic radiopharmaceutical, a MRI contrast agent, ora X-ray contrast agent of claim 11 to a patient by injection orinfusion; (2) imaging the area of the patient wherein theatherosclerosis is located.
 55. A method of imaging restenosis in apatient comprising: (1) administering a diagnostic radiopharmaceutical,a MRI contrast agent, or a X-ray contrast agent of claim 11 to a patientby injection or infusion; (2) imaging the area of the patient whereinthe restenosis is located.
 56. A method of imaging cardiac ischemia in apatient comprising: (1) administering a diagnostic radiopharmaceutical,a MRI contrast agent, or a X-ray contrast agent of claim 11 to a patientby injection or infusion; (2) imaging the area of the myocardium whereinthe ischemic region is located.
 57. A method of imaging myocardialreperfusion injury in a patient comprising: (1) administering adiagnostic radiopharmaceutical, a MRI contrast agent, or a X-raycontrast agent of claim 11 to a patient by injection or infusion; (2)imaging the area of myocardium wherein the reperfusion injury islocated.